The use of enolase inhibitor pomhex for treatment of fibrosis

Abstract

The present invention provides methods for, and uses in, the treatment or prevention of fibrosis and fibrotic diseases comprising administering a composition comprising an enolase inhibitor such as POMHEX.

Description

[0001] Attorney Docket No.206085-0136-00WO TITLE OF THE INVENTION The Use of Enolase Inhibitor POMHEX for Treatment of Fibrosis CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 594,746, filed October 31, 2023, the contents of which are incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under HL121262 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Fibrosis is a major cause of morbidity and mortality in progressive fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) and leads to loss of organ function (Perelas, et al., 2020, The Lancet Respiratory Medicine. 8:304-320; Henderson, et al., 2020, Nature.587:555-566; Herzog, et al., 2014, 66:1967- 1978). Currently, there is no effective therapy for the treatment of fibrosis as the currently FDA-approved drugs reduce disease progression but do not reverse it (Boleto, et al., 2022, Therapeutic Advances in Musculoskeletal Disease.14:1759720X211066686; King, et al., 2014, New England Journal of Medicine.370:2083-2092; Richeldi, et al., 2014, New England Journal of Medicine.370:2071-2082; Khanna, et al., 2016, The Lancet. 387:2630-2640). Though lung transplantation is a viable option, it is only accessible to a small number of patients and its costs are prohibitive (Cheng, 2022, Stem Cell Research & Therapy.13:492; Cottin & Brown, 2019, Respiratory Research.20:13; Laporta Hernandez, et al., 2018, Medical Sciences.6:68). A major roadblock in the development of effective therapeutic strategies is incomplete understanding of disease mechanisms and mediators of fibrosis. Further elucidating those mechanisms could aid in the development of an effective anti-fibrotic Attorney Docket No.206085-0136-00WO therapy, which can stop the progression of fibrosis and reverse it, thereby significantly reducing the burden associated with fibrosing diseases. Thus, there is a need in the art for effective therapeutic strategies to treat and prevent fibrotic diseases. The present invention satisfies this unmet need. SUMMARY OF THE INVENTION In one aspect, the present invention relates to a composition for use in the treatment of fibrosis in a subject in need thereof, wherein the composition comprises an effective amount of POMHEX, or a POMHEX derivative, preferably POMHEX. In one embodiment, said fibrosis or fibrotic or fibrotic-related disease or disorder is selected from the group consisting of pulmonary fibrosis, interstitial lung diseases, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, familial pulmonary fibrosis, pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis, Coal workers' pneumoconiosis, asbestosis, bleomycin lung, sarcoidosis, silicosis, acute lung injury, acute respiratory distress syndrome (ARDS), combined pulmonary fibrosis and emphysema (CPFE), asthma; cardiac fibrosis, vascular fibrosis, endomyocardial fibrosis (EMF), atherosclerosis, aortic valve sclerosis (AVS); skin fibrosis and wound healing diseases or disorders, hypertrophic scars, keloid scars (keloids), scarring after surgery, systemic scleroderma, localized scleroderma, morphea, eosinophilic fasciitis; liver cirrhosis, hepatitis, metabolic dysfunction-associated steatohepatitis (MASH), congenital hepatic fibrosis, alcoholic liver disease, Hepatitis C Cirus (HCV)- or Hepatitis B Virus (HBV)-induced liver fibrosis, primary sclerosing cholangitis, primary biliary cirrhosis; kidney fibrosis, fibrotic nephropathies, IgA nephropathy, transplant nephropathy, diabetic nephropathy, lupus nephritis, glomerulonephritis, focal segmental glomerulosclerosis (FSGS); ocular fibrosis, capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis, subretinal fibrosis, dry eye, macular edema, retinopathy, glaucoma, age-related macular degeneration (AMD); fibrosis as a result of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis or Alzheimer’s disease; fibrosis as a result of Graft-Versus-Host Disease (GVHD), subepithelial fibrosis, uterine fibrosis, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, multifocal fibrosclerosis, rheumatoid arthritis, tumor-associated fibrosis, radiation- Attorney Docket No.206085-0136-00WO induced fibrosis, chemo-therapy induced fibrosis, systemic sclerosis, and Sjogren’s syndrome. In one embodiment, said fibrosis or fibrotic or fibrotic-related disease or disorder is pulmonary fibrosis, particularly idiopathic pulmonary fibrosis. In another embodiment, the subject having fibrosis has systemic scleroderma. In a further embodiment, the subject having fibrosis has a hypertrophic or keloid scar. In a still further embodiment, the subject having fibrosis has Peyronie’s disease. In one embodiment, the composition comprising POMHEX, or a POMHEX derivative, preferably POMHEX, is to be administered with a second agent or a second therapeutic agent, wherein the second agent or second therapeutic agent is an anti-fibrotic agent. In one embodiment, the subject is a non-primate mammal, preferably a dog, most preferably a West Highland White Terrier. In one embodiment, the subject is a human subject. In one aspect, the present invention relates to a method of reducing fibrosis, comprising contacting a group of cells or tissue with a composition comprising POMHEX, or a POMHEX derivative, preferably POMHEX, in an amount effective to reduce the fibrosis in said cells or tissue. In one embodiment, the tissue is pulmonary tissue. In some embodiments, the tissue is skin tissue. In one embodiment, the cells or tissue are maintained ex vivo. In some embodiments, the cells or tissue are contained within a subject in vivo. In one embodiment, the composition comprises POMHEX. In one embodiment, the present invention relates to a method of treating fibrosis, comprising administering a composition comprising POMHEX, or a POMHEX derivative, preferably POMHEX, to a subject having fibrosis in an amount effective to treat the fibrosis in said subject. In one embodiment, the subject having fibrosis has a fibrotic or fibrotic-related disease or disorder selected from the group consisting of pulmonary fibrosis, interstitial lung diseases, idiopathic pulmonary fibrosis (IPF), interstitial pulmonary fibrosis, familial pulmonary fibrosis, pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis, Coal workers' pneumoconiosis, asbestosis, bleomycin lung, sarcoidosis, silicosis, Attorney Docket No.206085-0136-00WO acute lung injury, fibrosing mediastinitis, acute respiratory distress syndrome (ARDS), combined pulmonary fibrosis and emphysema (CPFE), asthma; cardiac fibrosis, vascular fibrosis, endomyocardial fibrosis (EMF), atherosclerosis, aortic valve sclerosis (AVS); skin fibrosis and wound healing diseases or disorders, hypertrophic scars, keloid scars, scarring after surgery, systemic scleroderma, localized scleroderma, morphea, eosinophilic fasciitis, Dupuytren’s Contracture; liver cirrhosis, hepatitis, metabolic dysfunction-associated steatohepatitis (MASH), congenital hepatic fibrosis, alcoholic liver disease, Hepatitis C virus (HCV)- or Hepatitis B virus (HBV)-induced liver fibrosis, primary sclerosing cholangitis, primary biliary cirrhosis; kidney fibrosis, fibrotic nephropathies, IgA nephropathy, transplant nephropathy, diabetic nephropathy, lupus nephritis, glomerulonephritis, focal segmental glomerulosclerosis (FSGS); ocular fibrosis, capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis, subretinal fibrosis, dry eye, macular edema, retinopathy, glaucoma, age-related macular degeneration (AMD); fibrosis as a result of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis or Alzheimer’s disease; fibrosis as a result of Graft-Versus-Host Disease (GVHD), subepithelial fibrosis, uterine fibrosis, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, multifocal fibrosclerosis, rheumatoid arthritis, tumor-associated fibrosis, radiation-induced fibrosis, chemo-therapy induced fibrosis, systemic sclerosis, and Sjogren's syndrome. In one embodiment, the subject has idiopathic pulmonary fibrosis. In one embodiment, the subject has a hypertrophic or keloid scar. In one embodiment, the subject has systemic scleroderma. In one embodiment, the subject has Peyronie’s disease. In one embodiment, the composition comprises POMHEX. In one embodiment, the method further comprises administering to the subject an effective amount of a second therapeutic agent, wherein the second therapeutic agent is an anti-fibrotic agent. In one embodiment, the subject is a non-primate mammal, preferably a dog, most preferably a West Highland White Terrier. In one embodiment, the subject is a human subject. In one aspect, the present invention relates to a composition comprising a first anti-fibrotic agent, wherein the first anti-fibrotic agent is POMHEX, or a POMHEX Attorney Docket No.206085-0136-00WO derivative, preferably POMHEX, and a second, distinct anti-fibrotic agent, in a combined amount effective to treat fibrosis in a subject. In one aspect, the present invention relates to a therapeutic kit comprising, in at least a first suitable container, a first anti-fibrotic agent, wherein the first anti-fibrotic agent is POMHEX, or a POMHEX derivative, preferably POMHEX, and a second, distinct anti-fibrotic agent. In one such embodiment, the first anti-fibrotic agent is comprised in a first container, and the second, distinct anti-fibrotic agent is separately comprised in a second, distinct container. In one aspect, the present invention relates to the use of an effective amount of POMHEX, or a POMHEX derivative, preferably POMHEX, in the preparation of a medicament for treating fibrosis in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of preferred embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. Figure 1, comprising Figure 1A to Figure 1F, depicts the results of example experiments demonstrating that ENOBLOCK does not significantly reduce the expression of ECM genes in cellular lysates of normal lung fibroblasts. Normal human lung fibroblasts (n=3-4) were preincubated with DMSO or ENOBLOCK (1.68 µM) for one hour and then treated with TGF-β1 (10 ng / ml) for 72 hours to detect expression of ECM proteins. Figure 1A depicts protein levels of COL1α1 detected in cellular lysates of ENOBLOCK treated fibroblasts; Figure 1B depicts protein levels of FN detected in cellular lysates of ENOBLOCK treated fibroblasts; Figure 1C depicts protein levels of MMP-1 detected in cellular lysates of ENOBLOCK treated fibroblasts; Figure 1D depicts protein levels of MMP-3 detected in cellular lysates of ENOBLOCK treated fibroblasts; Figure 1E depicts protein levels of ENO monomer detected in cellular lysates of ENOBLOCK treated fibroblasts; and Figure 1F depicts protein levels of HMO-ENO Attorney Docket No.206085-0136-00WO detected in cellular lysates of ENOBLOCK treated fibroblasts. GAPDH is used as a loading control for cellular lysates. Quantitative analysis (Upper) and representative blots (Lower) are shown. Statistical analysis was performed using One-way ANOVA. There were no statistically significant differences in the ENOBLOCK treatment groups. Error bars are mean + / - SEM. Figure 2, comprising Figure 2A to Figure 2D, depicts the results of example experiments demonstrating that ENOBLOCK does not significantly reduce the expression of ECM genes in the conditioned media of normal lung fibroblasts. Normal human lung fibroblasts (n=3-4) were preincubated with DMSO or ENOBLOCK (1.68 µM) for one hour and then treated with TGF-β1 (10 ng / ml) for 72 hours to detect expression of ECM proteins. Figure 2A depicts protein levels of COL1α1 measured in the conditioned media of ENOBLOCK treated fibroblasts by immunoblotting; Figure 2B depicts protein levels of FN measured in the conditioned media of ENOBLOCK treated fibroblasts by immunoblotting; Figure 2C depicts protein levels of MMP-1 measured in the conditioned media of ENOBLOCK treated fibroblasts by immunoblotting; and Figure 2D depicts protein levels of MMP-3 measured in the conditioned media of ENOBLOCK treated fibroblasts by immunoblotting. Quantitative analysis (Upper) and representative blots (Lower) are shown. Statistical analysis was performed using One- way ANOVA. There were no statistically significant differences in the ENOBLOCK treatment groups. Error bars are mean + / - SEM. Figure 3, comprising Figure 3A to Figure 3E, depicts the results of example experiments demonstrating that ENO is required for YAP-1 and TWIST-1 expression. Control plasmid (C) and ENO containing plasmid (ENO) was transfected in normal lung fibroblasts (N=4) for 72 hours. Figure 3A depicts protein levels of YAP-1, detected in lysates by immunoblotting. Normal human lung fibroblasts (N=4-6) were treated with rENO protein (4 µg) for 72 hours. Figure 3B depicts immunoblotting done to measure the protein levels of YAP-1 in cellular lysates. Figure 3C depicts normal lung fibroblasts transfected with control or ENO specific siRNA (siENO) (30nM), 24 hours later, stimulated with TGF-β1 (10 ng / ml) and fibroblasts were harvested for protein fractionation after 72 hours. Nuclear fractions were extracted, and protein levels of YAP- 1 were detected by immunoblotting. Figure 3D depicts immunoblotting done to measure Attorney Docket No.206085-0136-00WO the protein levels of TWIST-1 (~80 kDa band) in cellular lysates. Figure 3E depicts normal lung fibroblasts transfected with control or ENO specific siRNA (siENO) (30nM), 24 hours later, stimulated with TGF-β1 (10 ng / ml) and fibroblasts were harvested for protein fractionation after 72 hours. Nuclear fractions were extracted, and protein levels of TWIST-1 were detected by immunoblotting. GAPDH and Tata-Binding Protein (TBP) or Histone H3 (HisH3) were used as loading control for lysates and nuclear fraction, respectively. Quantitative analysis (Upper) and representative blots (Lower) are shown. Statistical analysis was performed using Student’s t-test and One-way ANOVA as appropriate. *p < 0.05, ** p < 0.01. Error bars are mean + / - SD. Figure 4, comprising Figure 4A to Figure 4C, depicts the results of example experiments demonstrating that ENO and YAP-1 crosstalk regulates fibrotic phenotype in vitro. Normal lung fibroblasts were transfected with control or ENO specific siRNA (siENO) (30nM) and 24 hours later, stimulated with TGF-β1 (10 ng / ml).72 hours later fibroblasts were harvested, and cytoplasmic fractions were extracted and subjected to immunoblotting. Figure 4A depicts representative blots showing protein levels of FN, COL1α1, CTGF (38 kDa isoform), PAI-1 and α-SMA in cytoplasmic extracts. Figure 4B depicts representative blots showing protein levels of COL1α1, FN and PAI-1 in fibroblast conditioned media. Normal lung fibroblasts were transfected with control or YAP-1 specific siRNA (siYAP) (30 nM) for 24 hours and then stimulated with rENO (4 µg) for 48 hours.72 hours later, fibroblasts were harvested, and cellular lysates were subjected to immunoblotting. Figure 4C depicts representative blots showing protein levels of COL1α1 and PAI-1 in cellular lysates. GAPDH was used as loading control for lysates and cytoplasmic fractions. Quantitative analysis (Upper) and representative blots (Lower) are shown. Statistical analysis was performed using One-way ANOVA. *p < 0.05, ** p < 0.01. Error bars are mean + / - SD. Figure 5, comprising Figure 5A to Figure 5C, depicts the results of example experiments demonstrating that POMHEX reduces the expression of ECM genes in Normal lung fibroblasts. Normal human lung fibroblasts (n=4-5) were preincubated with DMSO or POMHEX (5µM) for one hour and then treated with TGF-β1 (10 ng / ml) for 48 and 72 hours to detect mRNA and protein levels, respectively. Figure 5A depicts mRNA expression levels of fibrosis related genes COL1A1, COL1A2, FN and ACTA2, which Attorney Docket No.206085-0136-00WO were measured relative to housekeeping gene B2M. Protein levels of ECM proteins were analyzed by immunoblotting. Figure 5B depicts representative blots showing protein levels of FN, COL1α1, COL1α2, CTGF and α-SMA in cellular lysates. Figure 5C depicts representative blots showing protein levels of FN, COL1α1, COL1α2 and MMP-1 in conditioned media. GAPDH and Ponceau S stain are used as a loading control for lysates and media, respectively. Quantitative analysis (Upper) and representative blots (Lower) are shown Statistical analysis was performed using One-way ANOVA. *p < 0.05, ** p < 0.01, **** p < 0.0001. Error bars are mean + / - SD. Figure 6, comprising Figure 6A to Figure 6D, depicts the results of example experiments demonstrating that POMHEX reduces the expression of ECM genes in lung fibroblasts from SSc patients. SSc lung fibroblasts (n=3-4) were treated with DMSO or POMHEX (5-10µM). mRNA expression and protein levels were measured after 48 and 72 hours, respectively. Figure 6A depicts mRNA expression levels of COL1A1, COL1A2, FN and ACTA2, measured relative to housekeeping gene B2M. Figure 6B depicts protein levels of COL1α1, COL1α2, FN, α-SMA and CTGF in cellular lysates measured relative to housekeeping protein GAPDH. Figure 6C depicts protein levels of FN, COL1α2, MMP-1 and MMP-3 in fibroblast conditioned media measured relative to PonceauS. Figure 6D depicts COL1α1 at 10 µM POMHEX in fibroblast conditioned media relative to PonceauS. Quantitative analysis (Upper) and representative blots (Lower) are shown. GAPDH and Ponceau S stain are used as a loading control for lysates and media, respectively. Statistical analysis was performed using Student’s t-test. *p < 0.05, ** p < 0.01, *** p < 0.001. Error bars are mean + / - SD. Figure 7, comprising Figure 7A to Figure 7H, depicts the results of example experiments demonstrating that POMHEX decreases YAP1 expression and HMW-ENO expression in human lung fibroblasts and SSc fibroblasts. Normal and SSc lung fibroblasts (n=3-5) were treated with 5 µM POMHEX. Normal lung fibroblasts were stimulated with TGF-β1 (10 ng / ml) one-hour post POMHEX treatment and harvested after 72 hours for probing cellular lysates and subcellular fractions. Figure 7A depicts protein levels of YAP-1 analyzed in cellular lysates of normal lung fibroblasts. Figure 7B depicts protein levels of YAP-1 analyzed in cellular lysates of SSc lung fibroblasts. Figure 7C depicts expression of YAP-1 assessed in cytoplasmic fractions of normal and Attorney Docket No.206085-0136-00WO SSc lung fibroblasts. Figure 7D depicts expression of YAP-1 assessed in nuclear fractions of normal and SSc lung fibroblasts. Normal human lung fibroblasts (n=3) were treated with TGF-β1 (10 ng / ml) for 72 hours and nuclear fraction was extracted. Figure 7E depicts nuclear extracts analyzed by immunoblotting for HMW-ENO protein expression. Unstimulated lung fibroblasts derived from normal lung donors (NL=5), patients with SSc (SScL=5) and patients with IPF (IPF=4) were cultured for 72 hours. Figure 7F depicts cellular lysates subjected to immunoblotting and protein levels of ENO and HMW-ENO were measured. POMHEX treated Normal lung fibroblasts and POMHEX treated SSc fibroblasts were harvested for immunoblotting. Figure 7G depicts protein levels of ENO and HMW-ENO in normal lung fibroblasts stimulated with TGF- β1 and treated with POMHEX. Figure 7H depicts protein levels of ENO and HMW-ENO in SSc fibroblasts treated with POMHEX assessed by immunoblotting. Quantitative analysis (Upper) and representative blots (Lower). GAPDH and PonceauS, HisH3 or TBP are used as a loading control for lysates and nuclear extracts. Statistical analysis was performed using One-way ANOVA and Student’s t-test as appropriate. *p < 0.05, ** p < 0.01, *** p < 0.001. Error bars are mean + / - SD. Figure 8, comprising Figure 8A to Figure 8C, depicts the results of example experiments demonstrating that POMHEX decreases fibrosis in mouse lungs. PBS (n = 6), DMSO with PBS (n=7), BLM with DMSO (n =7) (1.2 mU / g), or BLM with POMHEX (n=10) (10 mg / Kg) were administered intratracheally to C57BL / 6J mice. Lung tissues were collected after 14 days. Figure 8A depicts lung sections of BLM or BLEO and POMHEX treated mice were stained with Masson Trichrome blue stain. Scale bar= 100 µM. Figure 8B depicts mRNA expression levels of ECM genes Col1a1, Col1a2, Fn, Acta2 and Eno were measured relative to the housekeeping gene B2m. BLM=Bleomycin. Figure 8C depicts total collagen content in mouse lungs was quantified by Hydroxyproline assay. Statistical analysis was performed using One-way ANOVA. *p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Error bars are mean + / - SD. Figure 9, comprising Figure 9A to Figure 9C, depicts the results of example experiments demonstrating that ENO regulates the expression of TWIST-1 in vitro. Normal lung fibroblasts were transfected with control or ENO specific siRNA (siENO) Attorney Docket No.206085-0136-00WO (30nM) and 24 hours later, stimulated with TGF-β1 (10 ng / ml).72 hours later fibroblasts were harvested, and nuclear fractions were extracted and subjected to immunoblotting. Figure 9A depicts representative blots showing protein levels of ENO in nuclear extracts. Figure 9B depicts normal lung fibroblasts (N=4-6) were stimulated with rENO protein (4 µg) for 72 hours. Immunoblotting was done to measure the protein levels of TWIST-1 (~25 kDa band) in cellular lysates. Figure 9C depicts representative blot showing the protein levels of TWIST-1 in the chromatin fractions of ENO silenced and TGF-β1 stimulated fibroblasts. GAPDH and HisH3 are used as a loading control for cellular lysates and nuclear / chromatin extracts respectively. Quantitative analysis (Upper) and representative blots (Lower). Statistical analysis was performed using Student’s t-test and One-way ANOVA as appropriate. *p < 0.05, ** p < 0.01. Error bars are mean + / - SD. Figure 10 depicts the results of example experiments demonstrating that CTGF expression is downregulated in ENO silenced fibroblasts. Normal lung fibroblasts were transfected with control or ENO specific siRNA (siENO) (30nM) and stimulated with TGF-β1 (10 ng / ml), 24 hours later. Fibroblasts were harvested after 72 hours, and cytoplasmic fractions were extracted and subjected to immunoblotting. Representative blots showing protein levels of CTGF (35 kDa isoform) in cytoplasmic extracts. GAPDH is used as a loading control for cytoplasmic extracts. Quantitative analysis (Upper) and representative blot (Lower). Statistical analysis was performed using One-way ANOVA. Error bars are mean + / - SD. Figure 11 depicts the results of example experiments demonstrating that YAP-1 is significantly silenced in normal lung fibroblasts. Normal lung fibroblasts were transfected with 30nM of either control or YAP-1 specific siRNA (siYAP) for 24 hours and then stimulated with rENO (4 µg) for 48 hours. Fibroblasts were harvested 72 hours later, and cellular lysates were subjected to immunoblotting. Representative blots showing protein levels of YAP-1 in cellular lysates. GAPDH was used as loading control. Quantitative analysis (Upper) and representative blot (Lower) is shown. Statistical analysis was performed using One-way ANOVA. *p < 0.05, *** p < 0.001. Error bars are mean + / - SD. Figure 12 depicts the results of example experiments demonstrating that ENO isoform (~45 kDa) expression is similar in normal and patients’ derived fibroblasts at Attorney Docket No.206085-0136-00WO steady state. Untreated lung fibroblasts derived from normal lung donors (NL=5), patients with SSc (SScL=5) and patients with IPF (IPF=4) were cultured for 72 hours and cellular lysates were subjected to immunoblotting and protein levels of ENO was measured. Representative blot showing the steady state levels of ENO isoform (~45 kDa) in cellular lysates. GAPDH was used as loading control. Quantitative analysis (Upper) and representative blot (Lower) is shown. Statistical analysis was performed using One- way ANOVA. Error bars are mean + / - SD. Figure 13 depicts the results of example experiments demonstrating that L-Lactate levels were insignificantly changed in ENO silenced fibroblasts. Normal lung fibroblasts were transfected with control or ENO specific siRNA (siENO) (30nM), 24 hours later, stimulated with TGF-β1 (10 ng / ml) and conditioned media was harvested. Levels of L-Lactate were measured in the conditioned media. Quantitative analysis (Upper) and representative blot (Lower). Statistical analysis was performed using One-way ANOVA. Error bars are mean + / - SEM. Figure 14, comprising Figure 14A to Figure 14D, depicts the results of example experiments demonstrating that POMHEX effectively attenuates fibrosis in IPF fibroblasts. IPF lung fibroblasts (n=6) were treated with DMSO or POMHEX (5µM). Figure 14A depicts mRNA expression levels of COL1A1, COL1A2, FN, ACTA2 and MMP-1, measured after 48 hours relative to housekeeping gene B2M. Figure 14B depicts protein levels of FN, COL1α2 and α-SMA in fibroblast cellular lysates, analyzed after 72 hours by immunoblotting. Figure 14C depicts protein levels of FN and MMP-1 in fibroblast conditioned media, analyzed after 72 hours by immunoblotting. Figure 14D depicts protein levels of ENO and HMO-ENO measured in cellular lysates. Quantitative analysis (Upper) and representative blots (Lower) are shown. GAPDH and Ponceau S stain are used as a loading control for lysates and media, respectively. Statistical analysis was performed using Student’s t-test. *p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Error bars are mean + / - SEM. Figure 15 depicts the results of example experiments demonstrating that POMHEX reduces YAP-1 expression in IPF fibroblasts. IPF lung fibroblasts (n=6) were treated with DMSO or POMHEX (5µM). Protein levels of YAP-1 were assessed by immunoblotting. Quantitative analysis (Upper) and representative blots (Lower) are Attorney Docket No.206085-0136-00WO shown. GAPDH is used as a loading control. Statistical analysis was performed using Student’s t-test. ** p < 0.01. Error bars are mean + / - SEM. Figure 16, comprising Figure 16A to Figure 16C, depicts the results of example experiments demonstrating that HMW-ENO is a form of ENO triggered upon TGF-β1 stimulation and translocated to the nucleus. Normal human lung fibroblasts (n=3) were first treated with TGF-β1 (10 ng / ml) for 72 hours and the nuclear fraction was extracted. Figure 16A depicts the TGF-β1-stimulated nuclear fraction following incubation with anti-Citrinullated antibody or mouse IgG isotype, with bound HMO-ENO being analyzed using immunoblotting. Normal lung fibroblasts were next treated with the citrinullation enzyme inhibitors, AFM32a or GSK199, for 1 hour and later stimulated with TGF-β1 for 72 hours. Figure 16B depicts cellular lysates of the AFM32a-treated cells as analyzed by immunoblotting and Figure 16C depicts cellular lysates of the GSK199-treated cells as analyzed by immunoblotting. Quantitative analysis (Upper) and representative blots (Lower). GAPDH and TBP are used as a loading control for lysates and nuclear extracts. Statistical analysis was performed using One-way ANOVA and Student’s t-test as appropriate. *p < 0.05. Error bars are mean + / - SEM. Figure 17, comprising Figure 17A to Figure 17C, depicts the results of example experiments demonstrating that delayed POMHEX administration effectively reduces fibrosis in mouse lungs. PBS (n=8) or BLM (n =6) (1.2 mU / g) were administered intratracheally to C57BL / 6J male mice. On day 8, POMHEX was administrated to the BLM treated mice (n=7) (10 mg / Kg). DMSO was given to the PBS group. Lung tissues were collected after 21 days. Figure 17A depicts Masson Trichrome blue of lung sections of BLM or BLEO and POMHEX treated mice. Scale bar = 100 µM. Figure 17B depicts results from a hydroxyproline assay to quantify total collagen content in mouse lungs. Figure 17C depicts mRNA expression levels of ECM genes Col1a1, Col1a2, Fn and Eno, measured relative to the housekeeping gene B2m. BLM=Bleomycin. Statistical analysis was performed using One-way ANOVA. *p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Error bars are mean + / - SEM. Figure 18, comprising Figure 18A to Figure 18D, depicts comparative results of example experiments demonstrating that POMHEX significantly reduces the expression of ECM genes in normal lung fibroblasts compared to ENOBLOCK. Normal human lung Attorney Docket No.206085-0136-00WO fibroblasts (n=3-4) were preincubated with DMSO, POMHEX (5 µM) or ENOBLOCK (1.68 µM) for one hour and then treated with TGF-β1 (10 ng / ml) for 72 hours to detect expression of ECM proteins. Figure 18A depicts protein levels of FN, COL1α1 and HMO-ENO detected in cellular lysates of POMHEX treated fibroblasts; and Figure 18B depicts protein levels of FN, COL1α1 and HMO-ENO detected in cellular lysates of ENOBLOCK treated fibroblasts. Figure 18C depicts protein levels of FN, COL1α1 and MMP-1 measured in the conditioned media of POMHEX treated fibroblasts by immunoblotting; and Figure 18D depicts protein levels of FN, COL1α1 and MMP-1 measured in the conditioned media of ENOBLOCK treated fibroblasts by immunoblotting. GAPDH and PonceauS are used as a loading control for cellular lysates and conditioned media (POMHEX treated fibroblasts), respectively. Quantitative analysis (Upper) and representative blots (Lower) are shown. Statistical analysis was performed using One-way ANOVA. *p < 0.05, ** p < 0.01, **** p < 0.0001. Error bars are mean + / - SEM. DETAILED DESCRIPTION In one aspect, the present invention is directed to methods for, and uses in the, treatment, inhibition, prevention, or reduction of fibrosis. In one embodiment, the methods and uses comprise administering a composition comprising an enolase inhibitor, preferably an inhibitor of higher molecular weight enolase (HMW-ENO), a form of enolase of about 70 kDa, which translocates to the nucleus during fibrosis. In one preferred embodiment, the enolase inhibitor is POMHEX or a POMHEX derivative, preferably POMHEX. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods, uses and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, uses and materials are described. Attorney Docket No.206085-0136-00WO As used herein, each of the following terms has the meaning associated with it in this section. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods and uses. The term “abnormal” when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components thereof that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from those organisms, tissues, cells or components thereof that display the “normal” (expected) respective characteristic. Characteristics which are normal or expected for one cell or tissue type, might be abnormal for a different cell or tissue type. As used herein, to “alleviate” a disease or disorder, such as fibrosis, means reducing the frequency or severity of at least one sign or symptom of a disease or disorder. A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced. As used herein, “autologous” refers to a biological material derived from the same individual into whom the material will later be re-introduced. As used herein, “allogeneic” refers to a biological material derived from a genetically different individual of the same species as the individual into whom the material will be introduced. The terms “cells” and “population of cells” are used interchangeably and refer to a plurality of cells, i.e., more than one cell. The population may be a pure population comprising one cell type. Alternatively, the population may comprise more than one cell type. In the present invention, there is no limit on the number of cell types that a cell population may comprise. Attorney Docket No.206085-0136-00WO A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. An “effective amount” or “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered. An “effective amount” of a delivery vehicle is that amount sufficient to effectively bind or deliver a compound. As used herein “endogenous” refers to any material from or produced inside an organism, cell, tissue or system. As used herein, the term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system. The term “expression” as used herein is defined as the transcription and / or translation of a particular nucleotide sequence driven by its promoter. The term “inhibit,” as used herein, means to suppress or block an activity or function by at least about ten percent relative to a control value. Preferably, the activity is suppressed or blocked by 50% compared to a control value, more preferably by 75%, and even more preferably by 95%. “Isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods and uses described herein. In certain non-limiting embodiments, the patient, subject or individual is a human, dog, or cat, preferably a human. Attorney Docket No.206085-0136-00WO “Parenteral” administration of a composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), or intrasternal injection, or infusion techniques. A “tissue-specific” promoter is a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, “treating a disease or disorder” means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein. To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject. Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. The term “isomers” or “stereoisomers” refer to compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. The term “prodrug” refers to compounds that differ in structure from the reference molecule, but is chemically modified by a particular cellular process to ultimately become modified to retain the essential properties of the reference molecule or become the reference molecule. Attorney Docket No.206085-0136-00WO As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, Attorney Docket No.206085-0136-00WO solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the term “potency” refers to the dose needed to produce half the maximal response (ED50). As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay. Attorney Docket No.206085-0136-00WO “Measuring” or “measurement,” or alternatively “detecting” or “detection,” means assessing the presence, absence, quantity or amount (which can be an effective amount) of either a given substance within a sample, including the derivation of qualitative or quantitative concentration levels of such substances, or otherwise evaluating the values or categorization of the substance or the sample. As used herein, “associated” refers to coincidence with the development or manifestation of a disease, condition, or phenotype. Association may be due to, but is not limited to, genes responsible for housekeeping functions, those that are part of a pathway that is involved in a specific disease, condition, or phenotype and those that indirectly contribute to the manifestation of a disease, condition or phenotype. Description The present invention is based in part on the discovery that inhibiting enolase reduces fibrosis. Accordingly, in some embodiments the invention is directed towards treating fibrotic diseases. In some embodiments, the present invention provides methods of, and uses in, treating or preventing fibrosis or fibrotic or fibrotic-related diseases or disorders. In one embodiment, the methods and uses comprise administering a composition comprising an enolase inhibitor to a subject having fibrosis or a fibrotic or fibrotic-related disease or disorder. Preferably, the enolase inhibitor is an inhibitor of higher molecular weight enolase (HMW-ENO), a form of enolase of about 70 kDa, which translocates to the nucleus during fibrosis. Enolase inhibitors include, but are not limited to, SF2312 and derivatives thereof, including Pom-SF2312, PhAH and derivatives thereof, 3-Phospho-D-glyceric acid, POMSF, and HEX and derivatives thereof, such as POMHEX. Further enolase inhibitors include the mono-amidated phosphates or phosphonates and prodrugs of US Patent Application Publication No.2023 / 0167142 A1, incorporated by reference herein. In one preferred embodiment, the enolase inhibitor is POMHEX, a derivative of POMHEX, or pharmaceutically acceptable salts and hydrates thereof. POMHEX is a pivaloyloxymethyl (POM)-prodrug of HEX. In one embodiment, a derivative of POMHEX is a chemical compound that is structurally derived from the POMHEX compound through one or more Attorney Docket No.206085-0136-00WO steps, and maintains the ability of POMHEX to inhibit enolase, and particularly to inhibit the higher molecular weight form of enolase (HMW-ENO) in the nucleus, using, for example, the assays described herein in Example 2. In one embodiment, a derivative of POMHEX comprise HEX, prodrugs of HEX, or derivatives of HEX. POMHEX and exemplary derivatives are preferably described in US Patent No. 10,363,261, and also in US Patent Application Publication No. 2022 / 0089620, each incorporated by reference herein. In one embodiment, the enolase inhibitor is a compound of the formula: or a pharmaceutically acceptable salt, wherein: R1 is hydrogen, acyl(C^12) or substituted acyl(C^12); R2 is hydrogen, acyloxy(C^12), or substituted acyloxy(C^12); X1and X2are each independently O, S, or NRa, wherein: Ra is hydrogen, alkyl(C^6), or substituted alkyl(C^6); R3 and R4 are each independently hydrogen or alkyl(C^12), aryl(C^12), aralkyl(C^12), heteroaryl(C^12), heteroaralkyl(C^12), or a substituted version of these groups; or a phosphate protecting group; or R3 and R4 are taken together and are alkanediyl(C ^8)or substituted alkanediyl(C ^8); or —X3—R5; wherein: X3is a covalent bond, alkanediyl(C ^8), or substituted alkanediyl(C ^8); and R5 is acyl(C^18), alkoxy(C^18), —C(O)-alkoxy(C^18), acyloxy(C^18), or a substituted version of any of these groups; Attorney Docket No.206085-0136-00WO A1 is alkanediyl(C1-3); and Y1is hydrogen, amino, halo, hydroxy, phosphate, alkyl(C ^12), or substituted alkyl(C ^12). Relating to the above compound, in various independent embodiments, R1is hydrogen; R2 is acyloxy(C^8) or substituted acyloxy(C^8); R2 is hydrogen; and R3 is a phosphate protecting group, including wherein R3is a phosphate protecting group of the formula: -alkanediyl(C^6)-acyloxy(C^12) or substituted -alkanediyl(C^6)-acyloxy(C^12), and wherein R3 is pivaloyloxymethyl. Relating to the above compound, in certain embodiments, X1and X2are each O. Relating to the above compound, in various embodiments, R4 is a phosphate protecting group, including wherein R4is a phosphate protecting group of the formula: - alkanediyl(C^6)-acyloxy(C^12) or substituted -alkanediyl(C^6)-acyloxy(C^12), and wherein R4 is pivaloyloxymethyl. Relating to the above compound, in various independent embodiments, A1is -CH2-, -CH2CH2-, or -CH2CH2CH2-; and Y1is hydrogen. In one embodiment, the enolase inhibitor is a compound of the formula: Attorney Docket No.206085-0136-00WO wherein: R2is hydrogen, acyloxy(C ^12), or substituted acyloxy(C ^12); R3and R4are each independently hydrogen, alkyl(C ^12), substituted alkyl(C ^12), or a phosphate protecting group; and A1 is alkanediyl(C1-3); or wherein: R1is acyl(C ^12)or substituted acyl(C ^12); R2is acyloxy(C ^12), or substituted acyloxy(C ^12); R3is alkyl(C ^12), substituted alkyl(C ^12), or a phosphate protecting group; R4is hydrogen, alkyl(C ^12), substituted alkyl(C ^12), or a phosphate protecting group; and A1is alkanediyl(C1-3); or a pharmaceutically acceptable salt of either formula. In one embodiment, the enolase inhibitor is a compound of the formula:

[0002] Attorney Docket No.206085-0136-00WO wherein: R2is hydrogen; R3 and R4 are each independently hydrogen, alkyl(C^12), substituted alkyl(C^12), or a phosphate protecting group; and A1 is alkanediyl(C1-3); or a pharmaceutically acceptable salt thereof. In one embodiment, the enolase inhibitor is a compound of the formula: Attorney Docket No.206085-0136-00WO Attorney Docket No.206085-0136-00WO Attorney Docket No.206085-0136-00WO In one embodiment, the enolase inhibitor is a compound of the formula: Attorney Docket No.206085-0136-00WO Attorney Docket No.206085-0136-00WO 5 or a pharmaceutically acceptable salt of any of those formulas. In one embodiment, the enolase inhibitor is a compound of the formula:

[0003] Attorney Docket No.206085-0136-00WO or a pharmaceutically acceptable salt of any of those formulas. In certain preferred embodiments, the enolase inhibitor is POMHEX, of the formula: Attorney Docket No.206085-0136-00WO In one embodiment, fibrotic or fibrotic-related disease or disorders include, but are not limited to, pulmonary fibrosis, interstitial lung diseases, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, familial pulmonary fibrosis, pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis, Coal workers' pneumoconiosis, asbestosis, bleomycin lung, sarcoidosis, silicosis, acute lung injury, fibrosing mediastinitis, ARDS, combined pulmonary fibrosis and emphysema, asthma; cardiac fibrosis, vascular fibrosis, endomyocardial fibrosis, atherosclerosis, aortic valve sclerosis; skin fibrosis and wound healing diseases or disorders, hypertrophic scars, keloid scars (keloids), scarring after surgery, systemic scleroderma, localized scleroderma, including but not limited to morphea, eosinophilic fasciitis; liver (hepatic) cirrhosis, hepatitis, metabolic dysfunction-associated steatohepatitis, congenital hepatic fibrosis, alcoholic liver disease, HCV- or HBV-induced liver fibrosis, primary sclerosing cholangitis, primary biliary cirrhosis; kidney (renal) fibrosis, fibrotic nephropathies, IgA nephropathy, transplant nephropathy, diabetic nephropathy, lupus nephritis, glomerulonephritis, focal segmental glomerulosclerosis (FSGS); ocular fibrosis, capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis, subretinal fibrosis, dry eye, macular edema, retinopathy, glaucoma, age-related macular degeneration (AMD); fibrosis as a result of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis or Alzheimer’s disease; fibrosis as a result of Graft-Versus-Host Disease (GVHD), subepithelial fibrosis, uterine fibrosis, Peyronie’s disease, myelofibrosis (a bone marrow blood cancer), retroperitoneal fibrosis (or Ormond's disease, a disease of fibrosis in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and certain other structures), nephrogenic systemic fibrosis, multifocal fibrosclerosis, rheumatoid arthritis, tumor-associated fibrosis, radiation-induced fibrosis, chemo-therapy induced fibrosis, systemic sclerosis, and Sjogren’s syndrome. In one embodiment, interstitial lung diseases include, but are not limited to idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, connective tissue disease associated interstitial lung disease, Coal workers' pneumoconiosis, asbestosis, acute lung injury, fibrosing mediastinitis, and ARDS. Pulmonary fibrosis also includes pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a specific subgroup of Attorney Docket No.206085-0136-00WO pulmonary hypertension (PH), which is an elevation in the pressure in the arteries of the lungs and can result from many diseases. Pulmonary arterial hypertension is a disease of the blood vessels of the lungs involving fibrosis, meaning that these vessels have changed causing the elevation in pressure. Pulmonary fibrosis further includes combined pulmonary fibrosis and emphysema, which is an underrecognized fibrotic syndrome characterized by chronic, progressive disease with a poor prognosis. Subepithelial fibrosis, which contributes to airway remodeling, is also a key feature of asthma, which can thus be treated by the present invention. Indeed, lung fibrosis is a common occurrence in the pathogenesis of fatal and long-term asthma, and it is associated with disease severity and resistance to therapy. In one embodiment, skin fibrosis and wound healing diseases and disorders include, but are not limited to, hypertrophic scars, keloid scars (also termed “keloids”), scarring after surgery, systemic scleroderma, and localized scleroderma, including but not limited to morphea, as described in more detail below. Skin fibrosis also includes eosinophilic fasciitis, part of the spectrum of localized scleroderma or morphea, which involves the subcutis and fascia of the skin and is characterized by fascial thickening with an eosinophilic tissue infiltrate and peripheral eosinophilia. The eosinophils release TGF-β, which activates fibroblasts, resulting in increased expression of type I collagen, fibronectin, and tissue inhibitor of metalloproteinase-1 (TMIP-1), resulting in fibrosis. Skin fibrosis further includes Dupuytren’s Contracture, a fibrotic condition of the palmar fascia, the tissue under the skin of the palm and fingers. In one embodiment, fibrotic or fibrotic-related disease or disorders include, but are not limited to, cardiac fibrosis. In one embodiment, cardiac fibrosis results from a cardiac injury. For example, in one embodiment cardiac fibrosis results from an injury including, but not limited to, myocardial infarction, aortic stenosis, restrictive cardiomyopathy, systemic and pulmonary hypertension, or carcinoid heart disease. Cardiac fibrosis also includes vascular fibrosis, which is a widespread pathologic condition that arises during vascular remodeling in cardiovascular dysfunctions. Vascular fibrosis is characterized by endothelial matrix deposition and vascular wall thickening, and the RAAS and TGF-β / Smad signaling pathways are reportedly involved. Cardiac fibrosis further includes endomyocardial fibrosis, a form of restrictive cardiomyopathy, Attorney Docket No.206085-0136-00WO characterized by endocardial fibrosis of the apices and inflow tracts of the right ventricle, left ventricle or both, which can result in high morbidity and mortality in certain patient populations. Cardiac fibrosis contributes to other cardiovascular diseases, particularly atherosclerosis and aortic valve sclerosis, which are driven by persistently active resident fibroblasts, myofibroblasts, and smooth muscle cells, leading to excessive extracellular matrix secretion and tissue thickening of severe pathological consequence. In one embodiment, fibrosis (“pathogenic fibrosis”) includes the formation or development of excess fibrous connective tissue in an organ or tissue as an exaggerated reparative or reactive process, as opposed to a formation of fibrous tissue as a normal constituent of an organ or tissue (“healthy fibrosis”). All tissues and organs are susceptible to pathogenic fibrosis, with the liver, kidney and eyes being susceptible, and the skin and lungs being particularly susceptible to such fibrosis. In some instances, fibrotic diseases are characterized by the activation of fibroblasts, increased production of collagen and fibronectin, and transdifferentiation into contractile myofibroblasts. This process usually occurs over many months and years and can lead to organ dysfunction or death. Fibrotic-related diseases and disorders represents one of the largest groups of disorders for which there is no effective therapy and thus represents a major unmet medical need. Often the only redress for patients with fibrosis is organ transplantation; since the supply of organs is insufficient to meet the demand, patients often die while waiting to receive suitable organs. Lung fibrosis alone can be a major cause of death in scleroderma, lung disease, idiopathic pulmonary fibrosis, radiation- and chemotherapy-induced lung fibrosis and in conditions caused by occupational inhalation of dust particles. The invention may be practiced in any subject diagnosed with, or at risk of developing, fibrosis. Fibrosis is associated with many diseases and disorders. The subject may be diagnosed with, or at risk for developing interstitial lung disease including idiopathic pulmonary fibrosis, scleroderma, radiation-induced pulmonary fibrosis, bleomycin lung, sarcoidosis, silicosis, familial pulmonary fibrosis, an autoimmune disease or any disorder wherein one or more fibroproliferative matrix molecule deposition, enhanced pathological collagen accumulation, apoptosis and alveolar septal rupture with honeycombing occurs. The subject may be identified as having fibrosis or Attorney Docket No.206085-0136-00WO being at risk for developing fibrosis because of exposure to asbestos, ground stone, silica and metal dust, because of the administration of a medication, such as bleomycin, busulfon, pheytoin, and nitro furantoin, which are risk factors for developing fibrosis, or because of radiation such as in patients with head & neck cancer who develop fibrosis of the salivary glands. It is also contemplated that the compositions and methods and uses of the invention may be used in the treatment of organ fibrosis secondary to allogenic organ transplant, e.g., graft transplant fibrosis. Non-limiting examples include renal transplant fibrosis, heart transplant fibrosis, liver transplant fibrosis, etc. In certain embodiments, the methods and uses of the present invention are used to treat multiple fibrotic or fibrotic-related diseases or disorders with underlying causes including myocardial infarct, cirrhosis, hepatitis, etc. In other embodiments, the methods and uses of the invention are used to treat one named disease or disorder, which impacts multiple tissues. Nephrogenic systemic fibrosis, for example, is a syndrome that involves fibrosis of the skin, joints, eyes, and internal organs. Multifocal fibrosclerosis, as another example, is characterized by fibrous lesions co-occurring at a variety of sites, and includes mediastinal fibrosis and Riedel's thyroiditis. In one embodiment, liver (hepatic) cirrhosis diseases and disorders include, but are not limited to, hepatitis, including autoimmune hepatitis, and metabolic dysfunction- associated steatohepatitis. Metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non- alcoholic fatty liver disease (NAFLD), in which MASH indicates the presence of further liver inflammation and fibrosis, including advanced fibrosis, leading to cirrhosis and an increased risk of liver cancer. Liver fibrosis further includes congenital hepatic fibrosis and alcoholic liver disease. Excessive alcohol consumption causes a wide spectrum of liver disease, including liver fibrosis, cirrhosis and liver cancer. Moreover, alcohol consumption also accelerates liver fibrosis in patients with other types of liver diseases such as viral hepatitis and nonalcoholic fatty liver disease. Virtually all clinical complications of alcoholic liver disease occur in patients with established fibrosis and cirrhosis, thus making fibrosis a key parameter for treatment and prognosis of patients. Attorney Docket No.206085-0136-00WO In another embodiment, liver (hepatic) cirrhosis diseases and disorders include, but are not limited to, HCV- or HBV-induced liver fibrosis. Removal or elimination of the causative agent, particularly the control or cure of viral infection, has shown that certain liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications, particularly in advanced fibrosis. Thus, the present invention provides an important anti-fibrotic therapy to treat and / or prevent liver disease progression and HCC development in HCV- or HBV-infected subjects. In further embodiments, liver (hepatic) cirrhosis diseases and disorders include, but are not limited to, primary sclerosing cholangitis and primary biliary cirrhosis. Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disorder. Inflammation, fibrosis, and stricturing of intrahepatic or extrahepatic biliary ducts characterize PSC, which is usually a progressive disorder that leads to complications of cholestasis and liver failure. Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis and hepatic fibrosis, which progresses to cirrhosis and liver failure. The invention may be practiced in any subject diagnosed with, or at risk of developing, the skin fibrosis disease, scleroderma. Scleroderma is a chronic autoimmune disease characterized by fibrosis (or hardening), vascular alterations, and autoantibodies. There are two major forms: limited systemic scleroderma and diffuse systemic scleroderma. The cutaneous symptoms of limited systemic scleroderma affect the hands, arms and face. Patients with this form of scleroderma frequently have one or more of the following complications: calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly), internal organ fibrosis and telangiectasias. In some embodiments, the methods and uses of the present invention are used to treat subjects. “Subjects” include, but are not limited to, humans and other primates, mammals and non-primate mammals including commercially relevant mammals and pets such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs, and research animals such as rodents, rats and mice. Subjects may also be termed bovine, porcine, equine, ovine, feline, canine and murine. In certain embodiments, the subject to be Attorney Docket No.206085-0136-00WO treated is a domestic cat, which are known to be susceptible to idiopathic pulmonary fibrosis, and particularly susceptible to renal fibrosis, which causes feline chronic kidney disease (CKD). In certain embodiments, the subject to be treated is a West Highland White Terrier (or “Westie”), which are known to be particularly susceptible to pulmonary fibrosis and idiopathic pulmonary fibrosis, to the extent that this disease is also known as “Westie Lung Disease or WLD”. In certain preferred embodiments, the subject to be treated is a human subject. Diffuse systemic scleroderma is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys, esophagus, heart and / or lungs. Localized scleroderma, such as linear scleroderma and morphea, affects the skin but not the internal organs. The skin manifestations of scleroderma can be painful, can impair use of the affected area (e.g., use of the hands, fingers, toes, feet, etc.) and can be disfiguring. Skin ulceration may occur, and such ulcers may be prone to infection or even gangrene. The ulcerated skin may be difficult or slow to heal. Difficulty in healing skin ulcerations may be particularly exacerbated in patients with impaired circulation, such as those with Raynaud's phenomenon. Lung involvement is the leading cause of death in scleroderma patients, which exhibits high morbidity and mortality. In certain embodiments, the compositions, methods, and uses of the present disclosure are used to treat scleroderma, for example skin symptoms of scleroderma. In certain embodiments, treating scleroderma comprises treating skin ulceration, such as digital ulcers. The methods and uses of the invention can be used to reduce the fibrotic and / or inflammatory symptoms of scleroderma in affected tissue and / or organs. In addition to skin symptoms / manifestations, scleroderma may also affect the heart, kidney, lungs, joints, and digestive tract. In certain embodiments, treating scleroderma includes treating symptoms of the disease in any one or more of these tissues, such as by reducing fibrotic and / or inflammatory symptoms. Lung problems are amongst the most serious complications of scleroderma and are responsible for much of the mortality associated with the disease. The two predominant lung conditions associated with scleroderma are pulmonary fibrosis and pulmonary hypertension. A patient with lung involvement may have either or both Attorney Docket No.206085-0136-00WO conditions. Lung fibrosis associated with scleroderma is one example of pulmonary fibrosis that can be treated using the methods and uses of the invention. Scleroderma involving the lung causes scarring (pulmonary fibrosis). Such pulmonary fibrosis occurs in about 70% to > 90% of scleroderma patients, although its progression is typically slow, and symptoms vary widely across patients in terms of severity. For patients that do have symptoms associated with pulmonary fibrosis, the symptoms include a dry cough, shortness of breath, and reduced ability to exercise. About 16% of patients with some level of pulmonary fibrosis develop severe pulmonary fibrosis. Patients with severe pulmonary fibrosis experience significant decline in lung function and alveolitis. In certain embodiments, the methods and uses of the present invention include the use of enolase inhibitors to treat scleroderma, for example lung fibrosis associated with scleroderma. The methods and uses of the invention can be used to reduce the fibrotic symptoms of scleroderma in lung. For example, the methods and uses can be used to improve lung function and / or to reduce the risk of death due to scleroderma. Kidney involvement is also common in scleroderma patients. Renal fibrosis associated with scleroderma is an example of renal fibrosis that can be treated by the methods and uses of the present invention. As kidney (renal) fibrosis driven by the aberrant accumulation of extracellular matrix is the final common pathway of nearly all types of chronic repetitive injury in the kidney, and is thus a hallmark of chronic kidney disease, treating kidney fibrosis using the present invention also provides for the treatment of a range of fibrotic nephropathies, including IgA nephropathy, transplant nephropathy, diabetic nephropathy and lupus nephritis. Other kidney (renal) fibrotic diseases that can be treated by the invention include glomerulonephritis, a condition characterized by irreversible and progressive glomerular and tubulointerstitial fibrosis, which can result in chronic kidney disease and end-stage renal disease; and focal segmental glomerulosclerosis (FSGS), which presents as a morphological / histological pattern of injury recognized on kidney biopsy that is characterized by fibrotic lesions in glomeruli that are focal (less than 50% of all glomeruli affected on light microscopy) and segmental (less than 50% of the glomerular tuft affected). Attorney Docket No.206085-0136-00WO The eye or eyes are also susceptible to untoward fibrosis, i.e., ocular fibrosis. Therefore, the present invention can be used to treat various forms of ocular fibrosis, including capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis and subretinal fibrosis, as contribute to multiple prominent fibrotic or fibrotic-related ocular diseases or disorders including, but not limited to, dry eye, macular edema and diabetic macular edema, retinopathy and diabetic retinopathy, glaucoma, and particularly macular degeneration. In macular degeneration, particularly age-related macular degeneration (AMD) or neovascular age-related macular degeneration, retinal and subretinal fibrosis is well-known to result in gradual vision loss, leading to irreversible blindness. The present invention can also be used to treat ocular fibrosis in further fibrotic or fibrotic-related ocular diseases or disorders including proliferative vitreoretinopathy (PVR), retinopathy of prematurity (ROP), glaucoma filtration surgery failure, corneal scarring, conjunctival scarring, choroidal neovascularization, posterior capsule opacification (PCO), congenital fibrosis of the extraocular muscles (CFEOM), congenital cataract, Stargardt Disease, Usher Syndrome, retinitis pigmentosa, Stickler Syndrome, ocular mucous membrane pemphigoid (OMMP), Stevens-Johnson Syndrome (SJS), uveitis, epiretinal membranes, aniridia, Axenfeld-Rieger Syndrome, Fuchs’ endothelial dystrophy, Bietti’s crystalline dystrophy, Leber congenital amaurosis, Marfan Syndrome with ocular manifestations, Ehlers-Danlos Syndrome with ocular manifestations, Alport Syndrome with ocular manifestations, Fabry Disease with ocular manifestations, Neurofibromatosis Type 1 with ocular manifestations, tuberous sclerosis complex with ocular manifestations and Von Hippel-Lindau Disease with ocular manifestations. In still further embodiments, fibrotic or fibrotic-related diseases or disorders include diseases in which the fibrosis exists in conjunction with a neurodegenerative disease. The present invention can thus be used to treat various forms of neurodegenerative fibrotic diseases including, but not limited to, amyotrophic lateral sclerosis (ALS, also known as motor neuron disease (MND) or Lou Gehrig's disease), multiple sclerosis, or Alzheimer’s disease. There is also a reported association of fibrosis, particularly liver fibrosis, with cognitive decline in Parkinson’s disease, and so Parkinson’s disease can also be treated by the invention. Attorney Docket No.206085-0136-00WO Reproductive tissues and organs are further susceptible to unwanted fibrosis. The present invention can thus be used to treat various fibrotic or fibrotic-related reproductive diseases or disorders including, but not limited to, uterine fibrosis, prostate fibrosis, Peyronie’s disease, balanitis, and lichen sclerosis, most particularly, Peyronie’s disease. Urological tissues and organs are also subject to aberrant fibrosis. Accordingly, the present invention can be used to treat various fibrotic or fibrotic-related urological diseases or disorders including, but not limited to, bladder neck contracture, interstitial cystitis (also known as bladder pain syndrome), vesicoureteral reflux (VUR), ureteropelvic junction obstruction (UPJO), ureteral strictures, urethral strictures, urethral diverticulum, urethral caruncle, urethral prolapse, and urethral fistula. In certain embodiments, the methods and uses of the present invention include the use of enolase inhibitors to reduce fibrosis in a group of cells or tissue. In some embodiments, the tissue is cardiac tissue, skin (dermal) tissue, particularly keloid scar tissue, hepatic tissue, renal tissue, ocular tissue, neurological tissue, reproductive tissue, particularly Peyronie’s disease tissue or urological tissue, preferably pulmonary tissue or skin tissue. In some embodiments, the cells are fibroblasts, interstitial fibroblasts, myofibroblasts, fibrocytes, epithelial cells, endothelial cells, neutrophils, monocytes, macrophages, T cells, mesenchymal cells, pneumocytes, cardiomyocytes, skin cells, hepatocytes, hepatic stellate cells (HSCs), renal tubular epithelial cells, astrocytes or cancer cells, most particularly fibroblasts, and myofibroblasts. In some embodiments, the methods and uses of the present invention include the use of enolase inhibitors to reduce fibrosis in a group of cells or tissue ex vivo. In some embodiments, the methods and uses of the present invention include the use of enolase inhibitor to reduce fibrosis in a group of cells or tissue within a subject in vivo. Administration In certain embodiments, the methods and uses of the invention comprise administering an effective amount of a composition comprising an enolase inhibitor, preferably, a HMW-ENO enolase inhibitor, for example, POMHEX or a derivative thereof, to a subject diagnosed with, suspected of having, or at risk for developing fibrosis or a fibrotic or fibrotic-related disease or disorder. In some embodiments, the Attorney Docket No.206085-0136-00WO composition is contacted to a cell or tissue where fibrosis is present or at risk for developing. In one embodiment, the composition is administered systemically to the subject. The methods and uses of the invention can comprise administering an enolase inhibitor to a patient or subject in need in a wide variety of ways. Modes of administration include oral administration, inhalation, intraoperatively, intravenous, intravascular, intramuscular, subcutaneous, intracerebral, intraperitoneal, soft tissue injection, surgical placement, arthroscopic placement, and percutaneous insertion, e.g., direct injection, cannulation or catheterization. Any administration may be a single application of a composition of invention or multiple applications. Administrations may be to single site or to more than one site in the individual to be treated. Multiple administrations may occur essentially at the same time or separated in time. In certain embodiments of the methods and uses, the composition is administered during surgical resection or debulking of a tumor or diseased tissue (e.g., a fibrotic tissue). For example, in subjects undergoing surgical treatment of diseased tissue or tumor, the composition may be administered to the site in order to further treat the tumor, fibrosis, acute lung injury, or a combination thereof. In some embodiments, the composition comprising an enolase inhibitor may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the subject, and the type and severity of the subject’s disease, although appropriate dosages may be determined by clinical trials. When “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, disease type, extent of disease, and condition of the patient (subject). The administration of the enolase inhibitor may be carried out in any convenient manner, including by inhalation, injection, ingestion, transfusion, implantation, or transplantation. The compositions described herein may be administered to a patient by orally, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. Attorney Docket No.206085-0136-00WO In certain embodiments, methods of, and uses in, treating fibrosis or fibrotic or fibrotic-related diseases or disorders include administering an enolase inhibitor, preferably, a HMW-ENO enolase inhibitor, for example, POMHEX or a POMHEX derivative, to a subject having fibrosis, as part of a therapeutic regimen along with one or more other drugs, biologics, or therapeutic interventions appropriate for the treatment of fibrosis. In certain embodiments, the additional drug, biologic, or therapeutic intervention is appropriate for particular symptoms associated with fibrosis. In such combination treatment embodiments, the methods and uses of the invention include administering to a subject having fibrosis at least a first composition comprising an effective amount of at least a first therapeutic agent or anti-fibrotic agent, wherein the at least a first therapeutic agent or anti-fibrotic agent is an enolase or HMW-ENO enolase inhibitor, preferably POMHEX or a POMHEX derivative, and further administering to the subject, optionally in at least a second composition, an effective amount of at least a second therapeutic agent or anti-fibrotic agent, wherein the at least a second therapeutic agent or anti-fibrotic agent is at least one other drug, biologic, or therapeutic intervention effective in the treatment of fibrosis, i.e., is at least a second, distinct anti-fibrotic agent. By way of example, an enolase inhibitor may be administered as part of a therapeutic regimen along with one or more immunosuppressive agents, such as methotrexate, cyclophosphamide, azathioprine, pirfenidone, nintedanib, tocilizumab, and mycophenolate mofetil. In certain embodiments, the additional drug, biologic, or therapeutic intervention appropriate for treating fibrosis is a C-terminal endostatin polypeptide of between 48 and 53 amino acids in length, as described in US Patent No.8,507,441, 8,716,232 or 10,709,769; or a C-terminal endostatin polypeptide of 9 amino acids in length, as described in US Patent No.9,365,616, 9,556,252 or 10,172,923; or a C-terminal endostatin polypeptide of 36 amino acids in length, as described in US Patent Application Publication No. US 2021 / 0008173; or a C-terminal endostatin polypeptide of between 14 and 34 amino acids in length, as described in Table 1 of PCT Patent Application Publication No. WO 2023 / 039399, each of the foregoing patents and publications being incorporated by reference herein. By way of further example, an enolase inhibitor may be administered as part of a therapeutic regimen along with one or more agents designed to increase blood flow, such Attorney Docket No.206085-0136-00WO as blood flow to ulcerated digits (e.g., nifedipine, amlodipine, diltiazem, felodipine, or nicardipine). By way of further example, an enolase inhibitor may be administered as part of a therapeutic regimen along with one or more agents intended to decrease fibrosis of the skin, such as d-penicillamine, colchicine, PUVA, Relaxin, and cyclosporine. By way of further example, an enolase inhibitor may be administered as part of a therapeutic regimen along with steroids or broncho-dilators. The invention encompasses administration of an enolase inhibitor, for example, POMHEX or a derivative thereof, for the treatment or prevention of fibrosis or fibrotic diseases and disorders. To practice the methods and uses of the invention; the skilled artisan would understand, based on the disclosure provided herein, how to formulate and administer the appropriate composition of the invention to a subject. The present invention is not limited to any particular method of administration or treatment regimen. Dosage and Formulation (Pharmaceutical compositions) In some embodiments, the present invention envisions treating fibrosis or a fibrotic or fibrotic-related disease or disorder and the like, in a mammal by the administration of a therapeutic agent, for example an enolase inhibitor. In one embodiment, the therapeutic agent is POMHEX or a derivative thereof. Administration of the therapeutic agent in accordance with the present invention may be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of the agents of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated. The amount administered will vary depending on various factors including, but not limited to, the composition chosen, the particular disease, the weight, the physical condition, and the age of the mammal, and whether prevention or treatment is to be achieved. Such factors can be readily determined by the clinician employing animal models or other test systems which are well known to the art. One or more suitable unit dosage forms having the therapeutic agent(s) of the invention can be administered by a variety of routes including parenteral, including by Attorney Docket No.206085-0136-00WO intravenous, intraperitoneal, subcutaneous, inhalation and intramuscular routes, as well as by direct injection into the diseased tissue. The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known to pharmacy. Such methods may include the step of bringing into association the therapeutic agent with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system. In various embodiments, the pharmaceutical compositions useful in the methods and uses of the invention may be administered, by way of example, systemically, subcutaneously, parenterally, or topically, such as, in oral formulations, inhaled formulations, including solid or aerosol, and by topical or other similar formulations. In addition to the appropriate therapeutic composition, such pharmaceutical compositions may contain pharmaceutically acceptable carriers and other ingredients known to enhance and facilitate drug administration. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer an appropriate modulator thereof, according to the methods and uses of the invention. When the therapeutic agents of the invention are prepared for administration, they are preferably combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form. The total active ingredients in such formulations include from 0.1 to 99.9% by weight of the formulation. A “pharmaceutically acceptable” is a carrier, diluent, excipient, and / or salt that is compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof. The active ingredient for administration may be present as a powder or as granules; as a solution, a suspension or an emulsion. Pharmaceutical formulations containing the therapeutic agents of the invention can be prepared by procedures known in the art using well known and readily available ingredients. The therapeutic agents of the invention can also be formulated as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous, or intravenous routes. Attorney Docket No.206085-0136-00WO The pharmaceutical formulations of the therapeutic agents of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension. Thus, the therapeutic agent may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small volume infusion containers or in multi-dose containers with an added preservative. The active ingredients may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. In certain embodiments, the composition of the invention is administered by inhalation. In certain embodiments, the invention is conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. In certain embodiments, the invention may take the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. The powdered or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 nanometers to about 2000 micrometers, and may further comprise one or more of the additional ingredients described herein. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units. Attorney Docket No.206085-0136-00WO Moreover, the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations. The pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are well-known in the art. Specific non- limiting examples of the carriers and / or diluents that are useful in the pharmaceutical formulations of the present invention include water and physiologically acceptable buffered saline solutions, such as phosphate buffered saline solutions pH 7.0-8.0. The agents of this invention can be formulated and administered to treat a variety of disease states by any means that produces contact of the active ingredient with the agent's site of action in the body of the organism. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic active ingredients or in a combination of therapeutic active ingredients. They can be administered alone but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium Ethylenediaminetetraacetic acid (EDTA). In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, a standard reference text in this field. The active ingredients of the invention may be formulated to be suspended in a pharmaceutically acceptable composition suitable for use in mammals and in particular, in humans. Such formulations include the use of adjuvants such as muramyl dipeptide derivatives (MDP) or analogs that are described in U.S. Patent Nos.4,082,735; 4,082,736; 4,101,536; 4,185,089; 4,235,771; and 4,406,890. Other adjuvants, which are Attorney Docket No.206085-0136-00WO useful, include alum (Pierce Chemical Co.), lipid A, trehalose dimycolate and dimethyldioctadecylammonium bromide (DDA), Freund’s adjuvant, and IL-12. Other components may include a polyoxypropylene-polyoxyethylene block polymer (Pluronic®), a non-ionic surfactant, and a metabolizable oil such as squalene (U.S. Patent No.4,606,918). Additionally, standard pharmaceutical methods can be employed to control the duration of action. These are well known in the art and include control release preparations and can include appropriate macromolecules, for example polymers, polyesters, polyamino acids, polyvinyl, pyrolidone, ethylenevinylacetate, methyl cellulose, carboxymethyl cellulose or protamine sulfate. The concentration of macromolecules as well as the methods of incorporation can be adjusted in order to control release. Additionally, the agent can be incorporated into particles of polymeric materials such as polyesters, polyamino acids, hydrogels, poly (lactic acid) or ethylenevinylacetate copolymers. In addition to being incorporated, these agents can also be used to trap the compound in microcapsules. Accordingly, the pharmaceutical composition of the present invention may be delivered via various routes and to various sites in a mammal body to achieve a particular effect (see, e.g., Rosenfeld et al., 1991; Rosenfeld et al., 1991a; Jaffe et al., supra; Berkner, supra). One skilled in the art will recognize that although more than one route can be used for administration, a particular route can provide a more immediate and more effective reaction than another route. Local or systemic delivery can be accomplished by administration comprising application or instillation of the formulation into body cavities, inhalation or insufflation of an aerosol, oral administration or by parenteral introduction, comprising intramuscular, intravenous, peritoneal, subcutaneous, intradermal, as well as topical administration. The active ingredients of the present invention can be provided in unit dosage form wherein each dosage unit, e.g., a teaspoonful, tablet, solution, or suppository, contains a predetermined amount of the composition, alone or in appropriate combination with other active agents. The term “unit dosage form” as used herein refers to physically discrete units suitable as unitary dosages for human and mammal subjects, each unit containing a predetermined quantity of the compositions of the present invention, alone Attorney Docket No.206085-0136-00WO or in combination with other active agents, calculated in an amount sufficient to produce the desired effect, in association with a pharmaceutically acceptable diluent, carrier, or vehicle, where appropriate. The specifications for the unit dosage forms of the present invention depend on the particular effect to be achieved and the particular pharmacodynamics associated with the pharmaceutical composition in the particular host. These methods and uses described herein are by no means all-inclusive, and further methods and uses to suit the specific application will be apparent to the ordinary skilled artisan. Moreover, the effective amount of the compositions can be further approximated through analogy to compounds known to exert the desired effect. The present invention further includes a number of Kits related to fibrosis. First provided are diagnostic, prognostic, and predictive therapy kits, which typically comprise one or more components known to be effective in the diagnosis or monitoring of fibrosis or a fibrotic-related disease or disorder, and further comprise at least a first enolase inhibitor, preferably POMHEX or a derivative thereof. These kits may include, e.g., pre- labeled antibodies in fully conjugated form for use in the detection of a marker or biomarker of fibrosis, preferably with instructions for use. Such kits may preferably further comprise control agents, such as suitably aliquoted biological compositions, whether labeled or unlabeled, as may be used to prepare a standard curve for a detection assay. The diagnostic, prognostic and predictive therapy kits may further comprise at least one or more other drugs, biologics, or therapeutic interventions appropriate for the treatment of fibrosis. Next provided are combination therapy kits, which typically comprise at least a first therapeutic agent or anti-fibrotic agent, wherein the at least a first therapeutic agent or anti-fibrotic agent is an enolase inhibitor, preferably a HMW-ENO enolase inhibitor, most preferably POMHEX or a derivative thereof, in combination with at least a second therapeutic agent or anti-fibrotic agent, wherein the at least a second therapeutic agent or anti-fibrotic agent is at least a second, distinct anti-fibrotic agent, i.e., at least one or more other drugs, biologics, or therapeutic interventions appropriate for the treatment of fibrosis. In general, the kits will contain the stated components in at least a first suitable container (or container means). The containers will generally include at least one vial, Attorney Docket No.206085-0136-00WO test tube, flask, bottle, syringe or other container or container means, into which the desired agents are placed and, preferably, suitably aliquoted. The kits will also typically include a means for containing the individual vials, or such like, in close confinement for delivery, such as, e.g., injection or blow-molded plastic containers into which the desired vials and other apparatus are placed and retained. The kits will preferably also include written or electronic instructions for use, e.g., in quantification, pre-clinical, clinical and / or veterinary embodiments, including for use in combined therapy. The components of the kits may be contained either in aqueous media or in lyophilized form. When reagents or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. The solvent may also be provided in another container within the kit. Any therapeutic components will preferably be in a pharmaceutically acceptable formulation, or ready for reconstitution as such. The kits may also contain a means by which to administer the therapeutic agents to an animal or patient, e.g., one or more needles or syringes, or an eye dropper, pipette, or other such like apparatus, from which the formulations may be injected into the animal or patient or applied to a diseased area of the body. The kits will preferably have distinct containers for each desired component or agent, particularly for the diagnostic, prognostic or predictive detection and diagnostic components. However, for use in combined therapies, the kits may comprise one container that contains two or more fibrosis therapeutics, pre-mixed; either in a molar equivalent combination, or with one component in excess of the other. Nonetheless, even the combination therapy kits will preferably comprise at least two distinct containers, a first container comprising at least one enolase inhibitor, preferably POMHEX or a derivative thereof, and at least a second container comprising one or more other drugs, biologics, or therapeutic interventions appropriate for the treatment of fibrosis. EXPERIMENTAL EXAMPLES The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be Attorney Docket No.206085-0136-00WO construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods and uses. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. Example 1: The enolase inhibitor ENOBLOCK does not reduce fibrosis. Fibrosis is a connective tissue disease characterized by excessive accumulation of extracellular matrix (ECM) components such as fibronectin and collagen in an organ or tissue and loss of ECM homeostasis (Thannickal, et al., 2014, The Journal of Clinical Investigation.124:4673-4677; Wynn & Ramalingam, 2012, Nature Medicine.18:1028- 1040). Fibrosis is an outcome of a dysregulated tissue repair response triggered by different factors. During normal wound healing, resident tissue fibroblasts differentiate to myofibroblasts and secrete inflammatory mediators. This results in transient accumulation of ECM components, in a positive feedback loop, facilitating the restoration of normal tissue architecture and maintaining tissue homeostasis (Henderson, et al., 2020, Nature.587:555-566; Cheng, et al., 2022, Stem Cell Research & Therapy. 13:492). However, when the wound healing process continues unchecked, it leads to dynamic accumulation of ECM components which cause disruption of tissue architecture and ultimately organ failure (Thannickal, et al., 2014 The Journal of Clinical Investigation.124:4673-4677). The most studied experimental fibrotic trigger is Transforming growth factor–β (TGF-β1). Other known inducers of fibrosis include PDGF, IL6, CTGF and IGF2 (Li, et al., 2022, Int J Biol Sci.18:5405-5414; Zhu, et al., 2022, Biomolecules.12:1622; Waldrep, et al., 2023, International Journal of Molecular Sciences.24:11234; Feghali, et al., 1992, J Rheumatol.19:1207-1211; Effendi & Nagano, 2022, International Journal of Molecular Sciences.23:6064; Paolini, et al., 2022, International Journal of Molecular Sciences.23:3904; Garrett, et al., 2019, PLOS ONE.14:e0225422). Although the role of Attorney Docket No.206085-0136-00WO SMAD and non-SMAD signaling in TGF-β1-mediated fibrosis have been the focus of extensive research, the role of glycolytic reprogramming in lung fibrosis is poorly understood.6-Phosphofructo-2-Kinase (PFKFB3), Pyruvate dehydrogenase kinase (PDK), Lactate dehydrogenase (LDH), Hexokinase2 (HK2), Glucose transporter 1 (GLUT1) are enzymes that mediate the effects of TGF ^ in lung fibrosis (Li, et al., 2022, Frontiers in Pharmacology.13:854544; Xie, et al., 2015, American Journal of Respiratory and Critical Care Medicine.192: 1462-1474; Yin, et al., 2019, Science Signaling. 12:eaax4067). Enolase (ENO) is an essential metalloenzyme that catalyzes the conversion of 2- phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis. Enolase is involved in various non-catalytic functions, referred to as ‘moonlighting’ functions, in the cell (Sharma, et al., 2021, JCI Insight.6:e146000; Huang, et al., 2022, Molecular Therapy – Oncolytics.24:288-298). Alterations of ENO expression is reported in different diseases including cancer, diabetes, and rheumatoid arthritis (Huang, et al., 2022, Molecular Therapy – Oncolytics.24:288-298; Cancemi, et al., 2019, International Journal of Molecular Sciences.20:3952; Didiasova, et al., 2019, Frontiers in Cell and Developmental Biology.7:61; Almaguel, et al., 2021, Frontiers in Genetics.11:614726; Qiao, et al., 2021, Int J Biol Sci.17:3981-3992). There are three ENO isoforms in mammalian tissues that have distinct tissue-specific roles: ENO1 is ubiquitously expressed in almost all tissues, ENO2 is a neuronal-specific isoform, and ENO3 is mainly expressed in muscles (Didiasova, et al., 2019, Frontiers in Cell and Developmental Biology.7:61). It has been shown that overexpression of ENO1 in primary fibroblasts increased the expression of profibrotic genes and downregulated the expression of anti-fibrotic matrix metalloproteases (MMP-1 and MMP-3) which degrade the matrix (Sharma, et al., 2021, JCI Insight. 6:e146000). The effects of ENO1 were independent of TGF-β1, unlike the effects of other glycolytic enzymes which are dependent on TGF ^. The profibrotic effect of ENO1 was also observed in vivo in murine lungs and ex vivo in human tissues in organ culture (Sharma, et al., 2021, JCI Insight. 6:e146000). The current example describes initial efforts to identify a small molecule ENO inhibitor for potential use as an inhibitor of fibrosis, and focuses on ENOBLOCK, a non- Attorney Docket No.206085-0136-00WO substrate analogue ENO inhibitor. ENOBLOCK directly binds and regulates the non- glycolytic ‘moonlighting’ functions of ENO. ENOBLOCK has shown activity in models of cancer treatment (US Patent No. 9,364,480). The Molecular Weight of ENOBLOCK is 594.62 g / mol., and the structure of ENOBLOCK is: The effect of ENOBLOCK was investigated in TGF- ^1 stimulated primary human lung fibroblasts. In the materials and methods used in these experiments, 2.0 x 105human lung fibroblasts were seeded in 6-well tissue culture plates in complete DMEM (DMEM, 10% FBS, 1X Ab / Am). Overnight serum starvation was done 24 hours later. Next day, cells were treated with 1.68 µM ENOBLOCK or equal volume of DMSO for 1 hour and then stimulated with 10 ng / ml human recombinant TGF- ^1 or vehicle control (VC) for TGF- ^1. The cells and conditioned media were harvested for analyzing proteins 72 hours after stimulation. The results focused on testing the efficiency of ENOBLOCK by analyzing the ECM expression at translational levels. It was found that ENOBLOCK had no significant effect in reducing the protein expression of COL1α1 and FN, the known fibrotic markers in cellular lysates (Figure 1A, Figure 1B) and in the media conditioned by fibroblasts (Figure 2A, Figure 2B). The expression of metalloproteinases MMP-1 and MMP-3, which are known to degrade matrix, was not significantly upregulated by ENOBLOCK in Attorney Docket No.206085-0136-00WO cellular lysates (Figure 1C, Figure 1D) and in conditioned media (Figure 2C, Figure 2D). Moreover, ENO monomer and HMW-ENO expressions were insignificantly downregulated by ENOBLOCK (Figure 1E, Figure 1F). In conclusion, overall, these data indicate that ENOBLOCK does not have a significant effect on fibrotic phenotype in primary human lung fibroblasts stimulated with TGF-β1. Example 2: The enolase inhibitor POMHEX reduces fibrosis in vitro and in vivo. As described in Example 1, ENO1 is known to exert profibrotic effects (Sharma, et al., 2021, JCI Insight. 6:e146000). The current example first shows that ENO1 triggers fibrosis by regulating the expression of a known transcriptional regulator of Hippo signaling, Yes-associated protein (YAP1). YAP1, along with its transcriptional coactivator with PDZ-binding motif (TAZ), are critical activators of fibrosis stimulated by TGF-β1. YAP senses the tissue stiffness caused by ECM deposition in fibrotic tissues and localizes to the cell nucleus, where it triggers fibrosis by a feed-forward loop mechanism (Enzo, et al., 2015, Embo j.34:1349-1370; He, et al., 2022, JCI Insight. 7:e146243). The current example next describes continuing activities that resulted in the identification of a small molecule ENO inhibitor that successfully inhibits fibrosis. Despite the lack of activity of ENOBLOCK, as shown in Example 1, ongoing studies showed that a different ENO inhibitor, POMHEX, is effective in reducing fibrosis. At low- nanomolar concentrations, POMHEX shows potency against ENO1-depleted cells in vitro and can eliminate ENO1-deleted xenografted tumors in vivo (Lin, et al., 2020, Nature Metabolism.2:1413-1426). The choice to test POMHEX was counterintuitive, given that POMHEX was designed to exert specificity for the neuronal-specific isoform ENO2 over ENO1 (Lin, et al., 2020, Nature Metabolism.2:1413-1426), whereas it is the ubiquitous ENO1 that exerts profibrotic effects. Nonetheless, the present experiments demonstrate for the first time that targeting Enolase via POMHEX attenuates fibrosis in primary lung fibroblasts, reverses fibrosis in lung fibroblasts isolated from patients with SSc and IPF and reduces / reverses fibrosis in the bleomycin murine model of pulmonary fibrosis, thus identifying POMHEX as an agent to treat fibrosis. Attorney Docket No.206085-0136-00WO The materials and methods used in the experiments are now described. Human primary lung fibroblasts Lung tissues were obtained from the explanted lungs of SSc and IPF patients who underwent lung transplantation, and normal controls whose lungs were not used for transplantation as previously reported (Hsu, et al., 2011, Arthritis Rheum.63:783-794). All tissues were obtained under an approved protocol and following written informed consent. Human primary lung fibroblasts were cultured from the lung tissues as previously described (Pilewski, et al., 2005, Am J Pathol.166:399-407). Briefly, approximately 3-5 mm2pieces of tissue were minced and fibroblasts were cultured and maintained in Dulbecco’s modified Eagle medium (DMEM) (Corning Incorporated Life Sciences, Tewksbury, MA, USA) supplemented with 10% fetal bovine serum (FBS) (Sigma-Aldrich, St. Louis, MO, USA), penicillin, streptomycin, and antimycotic agent (Invitrogen, Carlsbad, CA, USA). All cells were used between passages 3–8. Western blot analysis Cell lysates, subcellular fractions and conditioned media from fibroblast cultures were analyzed by immunoblotting as previously described (Cottin & Brown, 2019, Respiratory Research.20:13). Cell lysates were prepared by scraping the cells in 2X SDS-PAGE buffer, boiled and stored at -80°C. Conditioned media was prepared for SDS-PAGE by mixing with 6X SDS-PAGE buffer and processed as above. For the preparation of subcellular fractions, fibroblasts were trypsinized and cell pellets were harvested. Cytoplasmic, nuclear and chromatin fractions were extracted using subcellular fractionation kit (Thermo Fisher Scientific, Waltham, MA, USA) following the manufacturer’s instructions. Protease inhibitor cocktail and phosphatase inhibitor (Sodium Orthovanadate (Thermo Fisher Scientific, Waltham, MA, USA) were added to the buffers.6X SDS-PAGE buffer was added and samples were boiled and stored at - 80°C. Antibodies used were anti-human ENO1 antibody, Tata Binding protein (TBP) antibody, anti-human smooth muscle actin (α-SMA) antibody (Abcam, Waltham, MA, USA), anti-human collagen type I α-I (COL1α1) (CloudClone, Wuhan, Hubei, China) Attorney Docket No.206085-0136-00WO and type I α-II (COL1α2) antibody, anti-human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody, anti-human fibronectin (FN) antibody (Santa Cruz Biotech. Inc., Santa Cruz, CA, USA), anti-human PAI-1 antibody (Proteintech, Rosemont, IL, USA), anti-human V5 antibody (Sigma, St. Louis, MO, USA), human YAP-1 antibody, anti-human CTGF antibody (Millipore Sigma, Burlington, MA, USA), human YAP-1 antibody, TWIST-1 antibody, INHBA antibody, Thrombospondin-1 (THBS-1) antibody (Novus Biologics, Centennial, CO,USA), Histone H3 antibody (Cell signaling, Danvers, MA, USA), mouse IgG1 Isotype Control antibody, and Citrullinated enolase antibody (Cayman chemicals, Ann Arbor, MI, USA) as primary antibodies. Horseradish peroxidase-conjugated antibodies were used as a secondary antibody. Signals were detected using chemiluminescence. The proteins in the conditioned media were normalized using Ponceau S stain. Quantitative PCR Total RNA was extracted from mouse lung tissues and human fibroblasts using TRIZOL™ Lysis Reagent (phenol and guanidine isothiocyanate solution, Life technologies, CA, USA). Reverse transcription was performed with SuperScript™ Ⅳ (reverse transcriptase, Invitrogen, CA, USA). Gene mRNA expression levels were measured by quantitative PCR using the TaqMan®real-time PCR system (quantitative PCR system, Life Technologies) according to the manufacturer's protocol on a TaqMan®Gene Expression Assays Step One Plus real time PCR system (quantitative PCR system, Life technologies, CA, USA). Each gene's expression was measured as a ratio to the gene expression of B2M or B2m. Specific primers and probes for amplifying genes encoding Col1A1 (Hs00164004_m1), Col1A2 (Hs00164099_m1), FN (Hs00365052_m1), ACTA2 (Hs00426835_g1), B2M (Hs00187842_m1), Fn (Mm01256744_m1), Col1a1 (Mm00801666_g1), Col1a2 (Mm00483888_m1), Acta2 (Mm00725412_s1), Eno (Mm01619597_g1), B2m (Mm00437762_m1) were purchased from Life Technologies. Immunoprecipitation assay A total of 1 × 106 primary human lung fibroblasts were cultured on 10 cm dishes and were treated with TGF-β1 or VC. After 72 hours nuclear fractions of the fibroblasts Attorney Docket No.206085-0136-00WO were extracted using Subcellular Protein Fractionation Kit according to the manufacturer’s protocol. The nuclear fractions were incubated with citrullinated ENO antibody or mouse isotype control overnight on a rotator at 4°C. Next day, the complex was pulled down with agarose G beads (Thermoscientific) for 2 hours at 4°C. The immunoprecipitated proteins were subjected to SDS-PAGE and immunoblotting. In vitro POMHEX treatment Actively growing human primary human lung fibroblasts and fibroblasts from SSc patients were stimulated as previously described with some modifications (Nguyen, et al., 2018, Frontiers in Endocrinology. 9:601). Briefly, 2.0 x 105primary fibroblasts were seeded in 6-well tissue culture plates in compete DMEM. After 48 hours, the cells were serum-starved in DMEM for 1 hours prior to stimulation with POMHEX or equal volume of DMSO. Normal lung fibroblasts were stimulated with (0.001 to 5 uM) POMHEX or DMSO for 1 hour and then stimulated with 10 ng / ml human recombinant TGF- ^1 or PBS. SSc fibroblasts were treated with 5 and 10 uM POMHEX or DMSO. The cells and conditioned media were harvested 48 hours (for RNA) or 72 hours (for protein) after stimulation. The structure of POMHEX is shown below: Small interfering RNA (siRNA) transfection Primary human lung fibroblasts were seeded at a density of 2×105cells per well in six-well plates 24 hours prior to transfection with siRNA. Dharmacon™ ON- Attorney Docket No.206085-0136-00WO TARGETplus™ (modified siRNA for reducing off-target effects) ENO siRNA, YAP-1 siRNA, and control siRNA (siCTRL) were used (Lafayette, CO, USA). Transfection was done using Lipofectamine 2000 (Invitrogen, Grand Island, NY, USA) and Opti-MEM I Reduced-Serum Medium (Life Technologies) following the manufacturer’s recommendation. Briefly fibroblasts were transfected with 30nmol siRNA specific for ENO, YAP-1 or siCTRL for 24 hours in antibiotic and antimycotic-free DMEM media supplemented with 10% FBS. The media was replaced with serum-free DMEM. Two hours later, 10 ng / ml TGF-β1 or 3µg rENO was added to the wells transfected with siCTRL / siENO or siCTRL / siYAP-1, respectively. Fibroblasts were harvested after 72 hours. rENO treatment Normal lung fibroblasts were silenced with siCTRL or siYAP-1 as described above. After 24 hours the fibroblasts were stimulated with rEno (Abcam). The cells were serum starved 1 hour before rENO treatment. For each well, 4 μg rENO protein was added. Tris buffer (20 mM Tris-Hcl at pH 7.5, 1 mM MgSO4) was used as vehicle control. The fibroblasts were harvested 72 hours after siRNA transfection and processed protein extraction. Transfection of ENO expressing plasmid The ENO gene was subcloned into the mammalian plasmid OG1082 (Oxford Genetics) and expressed as a V5-tagged protein as described previously (Sharma, et al., 2021, JCI Insight. 6:e146000). Transfection was done using X-tremeGENE™ Transfection reagent (MilliporeSigma) as per manufacturer’s instructions. Briefly, human lung fibroblasts were seeded at a density of 1.5 × 105cells per well in 6-well plates (Corning). The culture media was replaced with antibiotic-free media 24 hours after seeding, and fibroblasts were transfected with 1 µg control empty vector (EV) or ENO- expressing plasmid. The cells were harvested 72 hours after transfection for immunoblotting. Attorney Docket No.206085-0136-00WO L-Lactate quantification L-Lactate was quantified from the conditioned media of SiENO or SiCTRL transfected and VC or TGF-β1 stimulated human lung fibroblasts using Glycolysis cell- based assay kit (Cayman Chemical) as per manufacturer’s instructions. In Vivo POMHEX treatment Under an approved protocol, pulmonary fibrosis was induced in mice as previously described (Yamaguchi, et al., 2012, Sci Transl Med.4:136ra171). Briefly, bleomycin (1.2mU / g body weight) was administrated oropharyngeally to 6-8-week-old male CB57BL / 6J mice (The Jackson Laboratory, Bar Harbor, ME, USA) in a total volume of 50 µl PBS. PBS alone was administered as a vehicle control. POMHEX (10 mg / kg mouse) or DMSO were administered oropharyngeally starting 24 hours after bleomycin and every third day for a total of four doses. Mice were sacrificed 14 days post treatment and lung tissues were collected. The four sets of treated mice were PBS / PBS, PBS / DMSO, Bleomycin / DMSO and PBS / POMHEX. For therapeutic studies, POMHEX or DMSO were administrated oropharyngeally 7 days after bleomycin treatment every third day (four doses in total). On day 21 after bleomycin treatment lungs were harvested. The three sets of treated mice were PBS / DMSO, Bleomycin / DMSO and PBS / POMHEX. Histological analysis Mice were sacrificed and left lungs were fixed in 10% formalin. Masson’s Trichrome staining was performed at AML laboratories (St. Augustine, FL). Images were captured on Axio Observer Microscope (Carl Zeiss Microscopy GmbH, Oberkochen, Germany). Hydroxyproline assay To quantify the amount of collagen in lung tissues, hydroxyproline content was measured as previously described with some modifications (Santos, et al., 2009, J Clin Invest.119:3613-3625). Briefly, the upper right lungs were dissolved in 1 ml 1N HCl at 105°C for 4 hours. The samples were cooled at room temperature and 20 µl of lysed clear Attorney Docket No.206085-0136-00WO samples were pipetted carefully into 96 wells plates and dried at 65°C for 2 hours. The standard was prepared by dissolving cis-4-Hydroxy-L-proline (Sigma) in 1mM HCl.100 µl chloramine-T was added to each well and incubated for 15 min at room temperature with shaking. Ehrlich’s solution (100 µl) was added to the wells and incubated for 15 min at 65°C for 15 minutes. The absorbance was measured at 550 nm. The hydroxyproline content in the samples was calculated automatically from the standard curve generated on a BioTek Synergy™ plate reader (Agilent, Santa Clara, CA). Statistics All continuous variables were expressed as the mean ± standard deviation. All statistical analyses were done using GraphPad Prism 9.00 for Windows, (GraphPad Software, La Jolla California USA, www. graphpad.com). Comparisons between 2 groups were tested for statistical significance with the paired t-test. Comparison among 3 or more groups was performed using ANOVA followed by Tukey’s multiple comparison test. Log transformations were applied based on normality and lognormality tests. The experimental results are now described. ENO1 upregulates the expression of YAP-1. YAP-1, a well-known transcription factor regulated in aerobic glycolysis, is considered a central regulator of the fibrotic response. Overexpression of YAP-1 promotes collagen production in lung fibroblasts and its knockdown inhibits ECM production (He, et al., 2022, JCI Insight.7:e146243). Using in vitro, ex vivo and in vivo assays, it was shown that ENO1 promotes lung fibrosis independently of TGF-β1 (Sharma, et al., 2021, JCI Insight. 6:e146000). To determine the role of YAP signaling in the fibrotic response to ENO, the effect of ENO on YAP-1 expression was tested by overexpressing ENO using plasmid transfection and by stimulating the fibroblasts with recombinant ENO (rENO). YAP-1 protein expression was increased in cellular lysates of ENO-overexpressing normal lung fibroblasts (Figure 3A) as well as in rENO-treated normal lung fibroblasts (Figure 3B). Upon TGF-β1 stimulation, YAP-1 localizes to the nucleus to activate the profibrotic genes. Therefore, the effect of ENO silencing on the Attorney Docket No.206085-0136-00WO nuclear translocation of YAP-1 was tested. ENO1 was silenced in human lung fibroblasts using siRNA followed by stimulation with TGF-β1. The fibroblasts were subjected to subcellular fractionation, and ENO levels in the nuclear fractions were analyzed. A significant silencing of ENO in the nuclear fractions was observed (Figure 9A). YAP-1 expression in nuclear fractions was significantly increased by TGF-β1 (Figure 3C), and a significant decrease in YAP-1 levels was observed in ENO-silenced and TGF-β1 stimulated fibroblasts as compared to siCTRL-transfected and TGF-β1 stimulated fibroblasts (Figure 3C). Together, these findings show that ENO1 regulates YAP-1 expression and its nuclear translocation. ENO1 increases TWIST-1 expression. The effect of ENO on Twist Family BHLH Transcription Factor 1 (TWIST-1) was investigated next. Studies have shown that YAP-1 upregulates pulmonary fibrosis by transcriptionally activating TWIST-1 in the nucleus. TWIST-1 is a transcription factor, and its expression is known to trigger epithelial to mesenchymal transition (EMT) and hence promote pulmonary fibrosis (Ning, et al., 2018, Journal of Cellular and Molecular Medicine.22:1383-1391; Chen, et al., 2019, Cell Death & Differentiation.26:1832- 1844). Its expression is also found to be elevated in patients with Idiopathic Pulmonary fibrosis (IPF) (King, et al., 2014, New England Journal of Medicine.370:2083-2092). Since YAP-1 regulates TWIST-1 expression and knockdown of ENO suppresses YAP-1 expression, the effect of ENO1 on TWIST-1 levels was examined. TWIST-1 expression levels were upregulated by rENO1 (Figure 3D, Figure 9B). TWIST-1 levels in the chromatic fraction of fibroblasts were increased by TGF-β1 stimulation, and ENO silencing decreased TWIST-1 levels (Figure 3E, Figure 9C), similarly to the effect observed on YAP-1. ENO promotes fibrosis via YAP1. To further investigate whether ENO regulates fibrosis via YAP-1, levels of ECM proteins were examined in cytoplasmic fractions and media of ENO1-silenced and TGF- β1-stimulated fibroblasts in which YAP-1 expression was downregulated. The protein levels of Collagen Type I Alpha 1 Chain (COL1α1), Collagen Type I Alpha 2 Chain Attorney Docket No.206085-0136-00WO (COL1α2), Fibronectin (FN) and plasminogen inhibitor activator-1 (PAI-1) were significantly downregulated in the cytoplasm (Figure 4A) and conditioned media (Figure 4B) of fibroblasts. Further, the expression of the myofibroblast marker alpha smooth muscle actin (α-SMA) was also significantly downregulated (Figure 4A). Interestingly, the protein expression of all these proteins were significantly decreased in ENO silenced cells independently of TGF-β1 (Sharma, et al., 2021, JCI Insight.6:e146000). Connective tissue growth factor (CTGF), a secreted matricellular protein, is known to activates myofibroblasts and promote ECM deposition in the affected organs (Lipson, et al., 2012, Fibrogenesis & Tissue Repair.5:S24). CTGF is a known downstream target protein of YAP-1, upregulated in various cancers (Zhang, et al., 2018, Molecular Cancer.17:134). Significant downregulation of CTGF expression was detected in ENO silenced and TGF-β1 stimulated fibroblasts (Figure 4A and Figure 10). Further, glycolysis assays were performed in fibroblasts silenced with SiENO and stimulated with TGF-β1 and no significant change was observed as compared to control fibroblasts (Figure 13). This suggests that ENO’s fibrotic activity is independent of its glycolytic function. Next, YAP-1 regulation of ENO mediated fibrosis was tested. YAP-1 was silenced in normal lung fibroblasts followed by stimulation with rENO protein. Significant silencing of YAP-1 was observed in fibroblasts (Figure 11). rENO significantly upregulated the expression of profibrotic proteins COL1 ^ ^ ^and PAI-1 in cellular lysates as expected (Figure 4C). Interestingly, rENO failed to induce the expression of COL1 ^ ^ ^and PAI-1 in YAP-1 silenced and rENO treated fibroblasts (Figure 4C). Together these data show that ENO and YAP-1 are functionally interdependent and alter each other’s role in fibrosis. The ENO inhibitor, POMHEX, attenuates fibrosis in normal lung fibroblasts. The effect of an ENO inhibitor, POMHEX, on pulmonary fibrosis was investigated. Primary lung fibroblasts were treated with POMHEX prior to stimulation by TGF-β1. POMHEX significantly attenuated the expression levels of the ECM genes COL1A1, COL1A2, FN and ACTA2 (Figure 5A) and protein levels of COL1α1, COL1α2, FN, α-SMA in cellular lysates (Figure 5B) and COL1α1, COL1α2 and FN in the media Attorney Docket No.206085-0136-00WO conditioned by the fibroblasts (Figure 5C). Changes in CTGF levels were not significant. The effect of POMHEX on MMPs was also tested. POMHEX significantly induced the expression of MMP-1 in the conditioned media of both untreated and TGF-β1 treated fibroblasts (Figure 5C), however, no significant effect on MMP-3 expression was observed. Overall, these results show that POMHEX reduces the fibrotic phenotype induced experimentally by TGF-β1 in primary lung fibroblasts from different donors. Notably, the identification of POMHEX as a small molecule ENO inhibitor that successfully inhibits fibrosis stands in contrast to the lack of anti-fibrotic activity of the first inhibitor tested, ENOBLOCK. Data showing the contrasting effectiveness of POMHEX over ENOBLOCK are provided for FN, COL1α1 and HMW-ENO in cellular lysates (compare Figure 18A to Figure 18B) and for FN, COL1α1 and MMP-1 in conditioned media (compare Figure 18C to Figure 18D) of POMHEX- and ENOBLOCK-treated fibroblasts. POMHEX attenuates the fibrotic response of SSc lung fibroblasts. The ability of POMHEX to reverse fibrosis was analyzed by testing the effects of POMHEX on primary fibroblasts derived from lung tissues of patients with systemic sclerosis (SSc), a prototypic fibrosing disease, who had severe lung disease and underwent lung transplantation. POMHEX efficiently downregulated the levels of COL1A1, COL1A2, FN and ACTA2 mRNA (Figure 6A) as well as protein levels of the corresponding proteins in fibroblast lysates (Figure 6B). CTGF expression was also significantly downregulated in the lysates (Figure 6B). Further, FN and COL1α2 were significantly downregulated and MMP-1 was significantly induced in SSc fibroblasts treated with POMHEX in the media conditioned by the fibroblasts (Figure 6C). Although there was a significant downregulation of COL1α1 in total lysates, a significant reduction in secreted levels of COL1α1 required a higher concentration of POMHEX (10 µM) (Figure 6D). These data suggest that POMHEX reverses the fibrotic phenotype of fibroblasts derived from patients with SSc with severe end-stage lung fibrosis. Attorney Docket No.206085-0136-00WO POMHEX attenuates the fibrotic response of IPF lung fibroblasts. Following the above results from advanced stage SSc fibroblasts, the effect of POMHEX was tested on fibroblasts derived from the lungs of IPF patients. POMHEX efficiently downregulated the levels of COL1A1, COL1A2, FN and ACTA2 mRNA (Figure 14A). The protein levels of COL1α2, FN and α-SMA were downregulated in fibroblasts lysates (Figure 14B) and secreted levels of FN were significantly low in the conditioned media (Figure 14C). Like SSc fibroblasts, there was a significant increase in the expression of secreted MMP-1 in conditioned media (Figure 14C). Contrary to SSc, COL1α1 was not downregulated by POMHEX at protein levels, both in lysates and conditioned media. Interestingly mRNA levels of COL1A1 were significantly low in IPF fibroblasts treated with POMHEX (Figure 14A). POMHEX regulates YAP-1 expression. ENO regulates YAP-1 expression. Since POMHEX is an ENO inhibitor, the effect of POMHEX on YAP-1 was examined. YAP-1 expression was significantly attenuated in POMHEX-treated normal (Figure 7A), SSc lung fibroblasts (Figure 7B) and IPF lung fibroblasts (Figure 15). POMHEX also significantly reduced levels of YAP-1 protein in both the cytoplasmic (Figure 7C) and nuclear fractions (Figure 7D) of normal and SSc lung fibroblasts, suggesting that its mechanism of action is, at least in part, via downregulation of YAP-1. TGF-β1 triggers ENO nuclear localization. ENO has been mostly studied as a cytoplasmic enzyme in glycolysis. However, ENO can translocate to different cell compartments and exert non-glycolytic functions (Terrier, et al., 2007, Autoimmunity Reviews.6:176-182; Pancholi, 2001, Cellular and Molecular Life Sciences CMLS. 58:902-920; Plow & Das, 2009, Blood.113:5371- 5372). Previous data reported a TGF-β1-independent non-glycolytic function of ENO. Since TGF-β1 is known to regulate the expression of some glycolytic enzymes, the effect of TGF-β1 on ENO expression or function was tested. In primary lung fibroblasts, TGF- β1 had no effect on the expression of monomeric ENO1 (45 kDa). However, TGF-β1 stimulation resulted in the detection of a higher molecular weight band (HMW-ENO) (70 Attorney Docket No.206085-0136-00WO kDa), potentially a dimer of ENO1, in the cellular lysates of TGF-β1-stimulated fibroblasts (Figure 7G). Further, the HMW-ENO was only detected in the nuclear fractions of TGF-β1-stimulated fibroblasts (Figure 7E), suggesting that TGF-β1 triggers the nuclear localization of ENO. The levels of HMW-ENO in unstimulated healthy fibroblasts and fibroblasts derived from the fibrotic lungs of patients with SSc and IPF were also examined. Fibroblasts derived from fibrotic lungs had significantly high levels of HMW-ENO compared to the healthy controls (Figure 7F, Figure 13), further pointing to the presence of an HMW-ENO in fibrosis. Next, immunoprecipitation was used to pull down HMO-ENO from the nuclear fractions of normal lung fibroblasts treated with TGF-β1 using citrinullated ENO antibody. When probed with ENO antibody, it was observed that HMW-ENO was pulled down by citrinullated ENO antibody (Figure 16A). This suggests that HMW-ENO is a citrinullated form of ENO triggered upon TGF-β1 stimulation which, when translocated to the nucleus, either undergoes dimerization or forms a complex with another protein not yet identified. To confirm this post-translational modification, inhibition experiments were performed using citrinullation enzyme Protein Arginase Deaminase (PAD) inhibitors: AFM32a (PAD2 inhibitor) and GSK199 (PAD4 inhibitor). It was observed that HMW-ENO expression was significantly downregulated by AFM32a (Figure 16B) as compared to GSK199 (Figure 16C) in cellular lysates of TGF-β1 stimulated lung fibroblasts, suggesting that ENO is citrinullated and citrinullation is PAD2 specific. POMHEX reduces HMW-ENO. The effect of POMHEX on HMW-ENO levels was then tested. POMHEX had no effect on levels of the 45kDa ENO monomer (Figure 7G), but it significantly reduced the levels of HMW-ENO triggered by TGF-β1 in normal lung fibroblasts. POMHEX had a similar effect on HMW-ENO levels in SSc fibroblasts (Figure 7H) and IPF fibroblasts (Figure 14D). Overall, these findings suggest that TGF-β1 promotes the nuclear localization of HMW-ENO and suggest that it is the HMW-ENO form of ENO (citrinullated, and possibly subject to other post-translational modifications) that mediates the fibrotic response. These findings also suggest that levels of HMW-ENO are reduced by POMHEX, correlating with the anti-fibrotic response of POMHEX in fibroblasts. Attorney Docket No.206085-0136-00WO POMHEX attenuates Bleomycin-induced lung fibrosis. The results from primary lung fibroblasts and fibroblasts derived from lungs of SSc and IPF patients showed that the ENO inhibitor POMHEX significantly downregulated ECM mRNA and protein levels. The effect of POMHEX was next tested in vivo in a murine bleomycin model of lung fibrosis. PBS or Bleomycin was administered to C57BL6 / J mice intratracheally with DMSO or POMHEX. Lung tissues were collected 14 days after Bleomycin treatment. POMHEX administration following bleomycin significantly reduced ECM deposition as assessed by Masson Trichrome Staining (Figure 8A) and significantly decreased hydroxyproline content (Figure 8C), in mouse lungs. The effect of POMHEX on mRNA expression of ECM genes in mouse lungs was also tested. POMHEX significantly reduced the bleomycin-induced expression of ECM genes Fn, Col1a1, Col1a2, Fn and Acta2 (Figure 8B). In addition, POMHEX significantly reduced expression levels of Eno transcripts (Figure 8B). These findings demonstrate that POMHEX is an ameliorates fibrosis in vivo. POMHEX reverses Bleomycin-induced lung fibrosis. To further explore the biological effectiveness of POMHEX, the effect of POMHEX in reversing the fibrosis in mice was evaluated. POMHEX or DMSO was administered to mice 7 days after bleomycin or PBS treatment and mice lungs were harvested 21 days after bleomycin treatment. Masson Trichrome staining showed that the POMHEX reduced fibrosis in the lungs however the effect was not significant (Figure 17A) as determined by Ashcroft score. However, POMHEX significantly reduced hydroxyproline content (Figure 17B). In addition, POMHEX significantly downregulated the mRNA expression levels of Fn, Col1a1 and Col1a2 (Figure 17C). In contrary to the 14 days mice experiment, there was no effect on Eno transcripts levels. Together these data in the bleomycin induced murine model of fibrosis show that POMHEX has potential in reversing fibrosis.

Claims

CLAIMS What is claimed is:

1. A composition for use in the treatment of fibrosis in a subject in need thereof, wherein the composition comprises an effective amount of POMHEX, or a POMHEX derivative.

2. The composition for the use of claim 1, wherein the composition is for use in the treatment of fibrosis in a subject having a fibrotic or fibrotic-related disease or disorder selected from the group consisting of pulmonary fibrosis, interstitial lung diseases, idiopathic pulmonary fibrosis (IPF), interstitial pulmonary fibrosis, familial pulmonary fibrosis, pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis, Coal workers' pneumoconiosis, asbestosis, bleomycin lung, sarcoidosis, silicosis, acute lung injury, fibrosing mediastinitis, acute respiratory distress syndrome (ARDS), combined pulmonary fibrosis and emphysema (CPFE), asthma; cardiac fibrosis, vascular fibrosis, endomyocardial fibrosis (EMF), atherosclerosis, aortic valve sclerosis (AVS); skin fibrosis and wound healing diseases or disorders, hypertrophic scars, keloid scars, scarring after surgery, systemic scleroderma, localized scleroderma, morphea, eosinophilic fasciitis, Dupuytren’s Contracture; liver cirrhosis, hepatitis, metabolic dysfunction-associated steatohepatitis (MASH), congenital hepatic fibrosis, alcoholic liver disease, Hepatitis C virus (HCV)- or Hepatitis B virus (HBV)-induced liver fibrosis, primary sclerosing cholangitis, primary biliary cirrhosis; kidney fibrosis, fibrotic nephropathies, IgA nephropathy, transplant nephropathy, diabetic nephropathy, lupus nephritis, glomerulonephritis, focal segmental glomerulosclerosis (FSGS); ocular fibrosis, capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis, subretinal fibrosis, dry eye, macular edema, retinopathy, glaucoma, age-related macular degeneration (AMD); fibrosis as a result of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis or Alzheimer’s disease; fibrosis as a result of Graft-Versus-Host Disease (GVHD), subepithelial fibrosis, uterine fibrosis, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, multifocalfibrosclerosis, rheumatoid arthritis, tumor-associated fibrosis, radiation-induced fibrosis, chemo-therapy induced fibrosis, systemic sclerosis, and Sjogren's syndrome.

3. The composition for the use of claim 2, wherein the composition is for use in the treatment of fibrosis in a subject having idiopathic pulmonary fibrosis.

4. The composition for the use of claim 2, wherein the composition is for use in the treatment of fibrosis in a subject having a hypertrophic or keloid scar.

5. The composition for the use of claim 2, wherein the composition is for use in the treatment of fibrosis in a subject having systemic scleroderma.

6. The composition for the use of claim 2, wherein the composition is for use in the treatment of fibrosis in a subject having Peyronie’s disease.

7. The composition for the use of any one of claims 1 to 6, wherein the composition comprises POMHEX.

8. The composition for the use of any one of claims 1 to 7, wherein the composition is to be administered with a second agent, wherein the second agent is an anti-fibrotic agent.

9. The composition for the use of any one of claims 1 to 8, wherein the subject is a non-primate mammal, preferably a dog.

10. The composition for the use of any one of claims 1 to 8, wherein the subject is a human subject.

11. A method of reducing fibrosis, comprising contacting a group of cells or tissue with a composition comprising POMHEX, or a POMHEX derivative, in an amount effective to reduce the fibrosis in said cells or tissue.

12. The method of claim 11, wherein the tissue is pulmonary tissue.

13. The method of claim 11, wherein the tissue is skin tissue.

14. The method of any one of claims 11 to 13, wherein the composition comprises POMHEX.

15. The method of any one of claims 11 to 14, wherein the cells or tissue are maintained ex vivo.

16. The method of any one of claims 11 to 14, wherein the cells or tissue are contained within a subject in vivo.

17. A method of treating fibrosis, comprising administering a composition comprising POMHEX, or a POMHEX derivative, to a subject having fibrosis in an amount effective to treat the fibrosis in said subject.

18. The method of claim 17, wherein the subject having fibrosis has a fibrotic or fibrotic-related disease or disorder selected from the group consisting of pulmonary fibrosis, interstitial lung diseases, idiopathic pulmonary fibrosis (IPF), interstitial pulmonary fibrosis, familial pulmonary fibrosis, pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis, Coal workers' pneumoconiosis, asbestosis, bleomycin lung, sarcoidosis, silicosis, acute lung injury, acute respiratory distress syndrome (ARDS), combined pulmonary fibrosis and emphysema (CPFE), asthma; cardiac fibrosis, vascular fibrosis, endomyocardial fibrosis (EMF), atherosclerosis, aortic valve sclerosis (AVS); skin fibrosis and wound healing diseases or disorders, hypertrophic scars, keloid scars, scarring after surgery, systemic scleroderma, localized scleroderma, morphea, eosinophilic fasciitis; liver cirrhosis, hepatitis, metabolic dysfunction-associated steatohepatitis (MASH), congenital hepatic fibrosis, alcoholic liver disease, Hepatitis C virus (HCV)- or Hepatitis B virus (HBV)- induced liver fibrosis, primary sclerosing cholangitis, primary biliary cirrhosis; kidney fibrosis, fibrotic nephropathies, IgA nephropathy, transplant nephropathy, diabetic nephropathy, lupus nephritis, glomerulonephritis, focal segmental glomerulosclerosis (FSGS); ocular fibrosis, capsular fibrosis, conjunctival fibrosis, corneal fibrosis, retinal fibrosis, subretinal fibrosis, dry eye, macular edema, retinopathy, glaucoma, age-related macular degeneration (AMD); fibrosis as a result of a neurodegenerative disease,amyotrophic lateral sclerosis (ALS), multiple sclerosis or Alzheimer’s disease; fibrosis as a result of Graft-Versus-Host Disease (GVHD), subepithelial fibrosis, uterine fibrosis, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, multifocal fibrosclerosis, rheumatoid arthritis, tumor-associated fibrosis, radiation- induced fibrosis, chemo-therapy induced fibrosis, systemic sclerosis, and Sjogren's syndrome.

19. The method of claim 18, wherein the subject has idiopathic pulmonary fibrosis.

20. The method of claim 18, wherein the subject has a hypertrophic or keloid scar.

21. The method of claim 18, wherein the subject has systemic scleroderma.

22. The method of claim 18, wherein the subject has Peyronie’s disease.

23. The method of any one of claims 17 to 22, wherein the composition comprises POMHEX.

24. The method of any one of claims 17 to 23, further comprising administering to the subject an effective amount of a second therapeutic agent, wherein the second therapeutic agent is an anti-fibrotic agent.

25. The method of any one of claims 17 to 24, wherein the subject is a dog.

26. The method of any one of claims 17 to 24, wherein the subject is a human subject.

27. A composition comprising a first anti-fibrotic agent, wherein said first anti-fibrotic agent is POMHEX, or a POMHEX derivative, and a second, distinct anti-fibrotic agent, in a combined amount effective to treat fibrosis in a subject.

28. A therapeutic kit comprising, in at least a first suitable container, a first anti-fibrotic agent, wherein said first anti-fibrotic agent is POMHEX, or a POMHEX derivative, and a second, distinct anti-fibrotic agent.

29. The kit of claim 28, wherein the first and second, distinct anti- fibrotic agents are comprised in a first and second distinct container.

30. Use of an effective amount of POMHEX, or a POMHEX derivative, in the preparation of a medicament for treating fibrosis in a subject in need thereof.

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