Use of farnesoid x receptor agonists in fibrosis

Abstract

This disclosure provides the use of a farnesoid X receptor (FXR) agonist in the preparation of a medicament for the prevention or treatment of pulmonary fibrosis. This disclosure demonstrates, both in vivo and in vitro, the anti-pulmonary fibrosis activity of the clinical-stage farnesoid X receptor (FXR) compound.

Description

Technical Field

[0001] This invention relates to the field of chemical medicine, and in particular to the application of farnesol X receptor agonists in pulmonary fibrosis. Background Technology

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease characterized by progressive extracellular matrix deposition, ultimately leading to respiratory failure and death. The pathogenesis of IPF involves several risk factors, including environmental exposure, smoking, chronic viral infections, and certain comorbidities. The pathological features of interstitial pulmonary fibrosis are honeycomb-like, traction bronchiectasis, and fibroblastic foci, representing abnormal remodeling of lung structure. Once the underlying pathology progresses to clinical and radiological abnormalities, the patient's prognosis is poor. Currently, treatment options for IPF patients remain limited, with lung transplantation being the only treatment that can significantly improve patient survival. After more than a decade of clinical trials, two drugs for IPF treatment—pirfenidone and nintedanib—have received FDA approval. While these two drugs can slow the decline in lung function in IPF patients, they do not improve survival or quality of life and have serious toxic side effects. Therefore, there is an urgent need to find new targets and drugs for treating pulmonary fibrosis. Summary of the Invention

[0003] To address at least one of the above problems, this invention discloses an in vivo and in vitro evaluation of the antifibrotic activity of multiple farnesoid X receptor (FXR) agonists, thereby screening out FXR agonists with good preventive and therapeutic effects on fibrosis, especially pulmonary fibrosis.

[0004] According to one aspect of the present invention, the use of a farnesoid X receptor agonist in the preparation of a medicament or formulation is provided for: (A1) preventing or treating fibrotic diseases; and / or, (A2) inhibiting the conversion of fibroblasts into myofibroblasts in vitro.

[0005] In some embodiments, the farnesoid X receptor agonist includes any one or more combinations of TERN101, Cilofexor, PX20606, Nidufexor, Omesdafexor (MET642), EDP305, Tropifexor, INT767, GW4064, or their precursors or pharmaceutically acceptable salts or derivatives thereof.

[0006] In some embodiments, the drug or preparation is used for one or more of the following: (B1) inhibiting the transformation of fibroblasts into myofibroblasts in vitro; (B2) inhibiting the expression of tissue fibrosis-related proteins; (B3) inhibiting tissue fibrosis-related signaling pathways; (B4) improving symptoms of tissue fibrosis; (B5) inhibiting or improving inflammation caused by tissue fibrosis; (B6) improving the survival rate of patients with tissue fibrosis; (B7) preventing or treating tissue fibrosis.

[0007] In some embodiments, the tissue fibrosis-related proteins include one or more of the following: fibronectin (Fn-1), type I collagen α1 (COL1A1), and α-smooth muscle actin (α-SMA).

[0008] In some embodiments, the inhibition of tissue fibrosis-related protein expression includes inhibiting the expression of tissue fibrosis-related proteins at both the transcriptional and translational levels.

[0009] In some embodiments, the tissue fibrosis-related signaling pathway is the TGF-β / SMAD signaling pathway.

[0010] In some embodiments, the farnesol X receptor agonist includes tablets, capsules, solutions, granules, pills, powders, ointments, pills, suspensions, powders, injections, suppositories, creams, sprays, or patches.

[0011] In some embodiments, the farnesoid X receptor agonist is administered via intramuscular injection, intranasal, intratracheal, gastric, rectal, mucosal presentation, intravenous delivery, or intradermal or subcutaneous administration.

[0012] In some embodiments, the fibrosis includes one or more of the following: renal fibrosis, pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, bone marrow fibrosis, adipose tissue fibrosis, pancreatic fibrosis, retroperitoneal fibrosis, mesenteric fibrosis, mammary fibrosis, cystic fibrosis, gastrointestinal tract fibrosis, or skin fibrosis.

[0013] In some embodiments, the fibrosis includes pulmonary fibrosis.

[0014] In some embodiments, the pulmonary fibrosis includes one or more of the following: idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, radiation-induced fibrosis, familial pulmonary fibrosis, silicosis, asbestos deposition, coal miner's pneumoconiosis, carbon monoxide poisoning, allergic pneumonia, interstitial lung disease, pulmonary hypertension or chronic obstructive pulmonary disease, nonspecific interstitial pneumonia, common interstitial pneumonia, and airway fibrosis.

[0015] In some embodiments, the symptoms of pulmonary fibrosis include one or more of the following: collagen deposition in the lungs, pulmonary scarring (fibrosis), organ parenchyma, and thickening of the alveolar walls.

[0016] According to one aspect of the present invention, an in vitro non-diagnostic, non-therapeutic method for inhibiting the transdifferentiation of lung fibroblasts into myofibroblasts is provided, comprising the step of contacting the lung fibroblasts with a therapeutically effective amount of the farnesol X receptor agonist.

[0017] Beneficial effects:

[0018] The farnesoid X receptor (FXR) agonist disclosed herein can inhibit the transcriptional activity of fibrosis-related genes and their protein expression to varying degrees, and can significantly improve fibrosis symptoms. The farnesoid X receptor agonist disclosed herein can be used to prepare drugs for the prevention or treatment of pulmonary fibrosis. Attached Figure Description

[0019] Figure 1 The TR-FRET assay demonstrates the in vitro activity of the FXR clinical compound.

[0020] Figure 2 The effects of RT-qPCR on the transcriptional activity of fibrosis-related genes by FXR clinical compounds are shown.

[0021] Figure 3 The study demonstrates the effect of Western blot analysis of FXR clinical compounds on the expression of fibrosis-related gene proteins.

[0022] Figure 4 The effects of FXR clinical compounds on the progression of pulmonary fibrosis in mice were demonstrated. Figure 4 A illustrates the experimental procedure; Figure 4 B shows the effect of the FXR clinical compound on the progression of pulmonary fibrosis in mice. Detailed Implementation

[0023] This invention primarily targets the farnesoid X receptor and investigates the pharmacological effects of a clinical-stage farnesoid X receptor compound on pulmonary fibrosis. It is the first time that the anti-pulmonary fibrosis activity of a clinical-stage farnesoid X receptor (FXR) compound has been demonstrated in vitro and in vivo.

[0024] This invention uses time-resolved fluorescence resonance energy transfer (TR-FRET) and luciferase reporter gene assays to demonstrate the activation effect of the compounds on the farnesoid X receptor (FXR). RT-qPCR was used to detect that a series of farnesoid X receptor (FXR) compounds could inhibit the mRNA levels of pulmonary fibrosis characterizing genes (FN-1, COL1A1, α-SMA). Western blot analysis showed that the farnesoid X receptor (FXR) compounds could inhibit the protein levels of pulmonary fibrosis characterizing genes (FN-1, COL1A1, α-SMA). This invention also uses a bleomycin (BLM)-induced pulmonary fibrosis mouse model to verify that the series of compounds provided in this invention that can activate the farnesoid X receptor (FXR) can delay the progression of pulmonary fibrosis in vivo and improve the symptoms of pulmonary fibrosis.

[0025] definition

[0026] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly used in the field to which this invention pertains. For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural forms, and vice versa.

[0027] Unless the context clearly indicates otherwise, the terms “a” and “an” as used herein include plural references.

[0028] The term "about" as used herein is as understood by one of ordinary skill in the art and varies within a certain range depending on the context in which it is used. If one of ordinary skill in the art is unfamiliar with the use of this term in the context in which it is used, "about" will mean a particular value plus or minus 10%.

[0029] The term "fibronectin (Fn-1)" used in this article refers to a multifunctional extracellular matrix protein and a high-molecular-weight glycoprotein. It can bind to various components on the cell surface and in the extracellular matrix, including collagen, fibrin, heparin, DNA, and actin, and is widely distributed on the cell surface, extracellular fluid, and basement membranes associated with connective tissue. Fn-1 possesses a wide range of biological activities, including promoting cell adhesion, cell-fiber and matrix connections, and phagocytic function of macrophages; it is also closely related to tissue healing, inflammation, fibrosis, and sclerosis. Therefore, changes in Fn-1 levels are closely related to the severity and prognosis of various clinical diseases.

[0030] The term "type I collagen α1 (COL1A1)" used in this article refers to a member of the collagen family that is involved in the epithelial-mesenchymal transition (EMT), which is closely related to the development of malignant tumors. Fibrotic fibroblasts are mainly enriched in fibrotic lesions and can be labeled with COL1A1.

[0031] The term "α-smooth muscle actin (α-SMA)" used in this article is encoded by the ACTA2 gene and is a subtype of vascular smooth muscle actin. It is mainly expressed in vascular smooth muscle cells and participates in vascular movement and contraction. In addition to being expressed in smooth muscle cells around the bronchi and large blood vessels, α-SMA is also expressed in fibroblasts, and its expression increases with the progression of pulmonary fibrosis.

[0032] The term "farnesoid X receptor (FXR)" used in this article belongs to the NR1H4 nuclear receptor family and plays an important role in regulating bile acid, glucose, lipid metabolism, and inflammatory responses. Bile acids are natural ligands of FXR, therefore FXR can also be referred to as a bile acid receptor.

[0033] The term "TR-FRET" used in this article refers to time-resolved fluorescence resonance energy transfer, a technique that combines fluorescence resonance energy transfer (FRET) and time-resolved (TR) methods. TR-FRET utilizes energy transfer from two fluorophores: a donor (a lanthanide element such as europium or terbium) and an acceptor (a fluorophore such as FITC or 5-FAM). The donor's emission spectrum overlaps with the acceptor's excitation spectrum. The donor is excited by an external energy source (e.g., a laser), and if it is within a sufficiently close distance to the acceptor, it can resonantly transfer energy to the acceptor. The acceptor is then excited, emitting light at a specific wavelength. Coupled to two biomolecules capable of specific binding, the binding of these biomolecules brings the donor and acceptor closer, resulting in energy transfer. TR technology leverages the unique properties of lanthanides in the rare earth elements, whose fluorescence lasts longer than ordinary fluorescence. The half-life of ordinary fluorescence is in the nanosecond range, while that of lanthanides is in the millisecond range, a difference of six orders of magnitude. Therefore, during detection, there is a time delay of approximately 100 microseconds in the TR (transient fluorescence) signal, making the ordinary background fluorescence signal in the reaction system almost zero. Thus, the background of TR is very low, accurately reflecting the actual situation of the sample.

[0034] As used herein, the terms "therapeutic effective amount (or dose)" or "effective amount (or dose)" refer to an amount of compound sufficient to cause a statistically significant improvement in one or more symptoms of the disease being treated. The precise amount depends on numerous factors, such as the activity of the composition, the method of delivery used, the immunostimulatory capacity of the composition, the intended patient and patient considerations, etc., and can be readily determined by those skilled in the art. Therapeutic effects may include, directly or indirectly, the reduction of one or more symptoms of the disease.

[0035] As used herein, the term "pharmaceuticalally acceptable" means that it can be administered to humans and / or other animals as subjects without producing excessive adverse reactions or side effects (such as toxicity, irritation, allergic reactions, etc.). The term "excipient" refers to auxiliary materials that coexist with the active ingredient in a pharmaceutical preparation without producing excessive adverse reactions or side effects, including carriers, osmotic pressure regulators, pH adjusters, diluents, disintegrants, excipients, solubilizers, stabilizers, preservatives, etc. The term "pharmaceuticalally acceptable excipient" refers to a highly safe excipient suitable for a specific pharmaceutical preparation and routinely used in pharmaceutical practice. This includes, but is not limited to, liposomes, liposomes, polymer micelles, nanostructured lipid carriers, solid lipid nanocarriers, mesoporous silica nanoparticles, etc.

[0036] The term "pharmaceutically acceptable salt" as used herein refers to, for example, metal salts and control amine salts, where the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be used in the separation or purification steps employed during preparation and are therefore covered within the scope of this invention.

[0037] The terms “pulmonary fibrosis,” “interstitial lung disease (ILD),” or “interstitial pulmonary fibrosis” as used in this article encompass more than 130 types of chronic lung diseases, named for their hardening of the lungs by damaging lung tissue, causing inflammation in the alveolar walls, and scarring or fibrosis of the pulmonary interstitium (the tissue between alveoli). Apnea is the first symptom of these diseases, and a dry cough may also occur. Symptoms and X-rays are often insufficient to accurately distinguish between different types of pulmonary fibrosis. In some patients with pulmonary fibrosis, the cause is known, while in others it is unknown or idiopathic. The course of this disease is generally unpredictable. Its progression includes thickening and hardening of lung tissue, inflammation, and dyspnea. Some patients require supplemental oxygen as part of their treatment. Pulmonary fibrosis typically includes any of the following features: (a) collagen deposition in the lungs, (b) pulmonary scarring (fibrosis) (including in the alveoli and interstitial spaces), and / or (c) the presence of areas of particularly thickened alveolar walls, one or more of which may contribute to chronic stiffening of the lungs and / or a decreased ability of the lung tissue to transport oxygen.

[0038] As used in this article, the term "subject" can refer to any organism capable of generating a cellular immune response, such as humans, pets, livestock, show animals, zoo specimens, or other animals. For example, a subject can be a human, a non-human primate, a dog, a cat, a rabbit, a rat, a mouse, a guinea pig, a horse, a cow, a sheep, a goat, a pig, etc.

[0039] As used herein, the term "treatment" refers to a method for obtaining a beneficial or desired outcome (including clinical outcomes) through the use of compounds or compositions of the present invention. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the severity and / or frequency of one or more symptoms caused by a disease, disorder, or condition; reducing the degree of a disease, disorder, or condition or causing its remission; stabilizing a disease, disorder, or condition (e.g., preventing or delaying the worsening of a disease, disorder, or condition); delaying or slowing the progression of a disease, disorder, or condition; improving the state of a disease, disorder, or condition; reducing the dosage of one or more other medicines required to treat a disease, disorder, or condition; and / or improving quality of life.

[0040] The term “effective dose” as used in this article refers to the effective dose and time period required to achieve the desired therapeutic or preventative effect.

[0041] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. The actual scope of protection of this invention is set forth in the claims. In the following description, descriptions of well-known structures and techniques are omitted to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications. Unless otherwise specified, the equipment, instruments, reagents, and / or kits used in the following embodiments are commercially available or obtained through conventional methods known to those skilled in the art.

[0042] Example

[0043] The compounds used in the examples and their structures are shown in Table 1.

[0044] Table 1: Structural Formulas of Compounds

[0045]

[0046]

[0047]

[0048] Example 1. Evaluation of the activity of clinical drugs targeting the farnesol X receptor using the TR-FRET assay.

[0049] Experimental procedure: Add phosphate buffer containing 0.005% Tween 20 (20mM Phosphate buffer (KH2PO4, K2HPO4) + 50mM KCl + 5mM TECP + 0.5mM EDTA) to an EP tube, then add His-FXR-LBD protein (amino acid sequence: MAHHHHHHVDDDDKMLEVLFQ) to a final concentration of 40nM. GPELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLILTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSDLLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEKLQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLCEIWDVQ, SEQ ID NO: 1), with a final concentration of 4 nM Anti-His-Tb (ThermoFisher, catalog number PV5863), and with a final concentration of 400 nM SRC2-2 accessory peptide (Nanjing Peptide Valley, sequence FITC-Ahx-LKEKHKILHRLLQDSSSPV, SEQ ID NO: 1), and a final concentration of 400 nM SRC2-2 accessory peptide (Nanjing Peptide Valley, sequence FITC-Ahx-LKEKHKILHRLLQDSSSPV, SEQ ID NO: 1). NO: 2), after slowly inverting and mixing, add 79.2 μL of the resulting mixed solution to each well of a 96-well plate; the second step is to prepare compounds with different concentration gradients. Dilute five compounds (TERN101, PX20606, tropifexor, Omesdafexor (MET 642), and EDP305) at an initial concentration of 2 mM in a 1:3 gradient to the 12th well, and add 0.8 μL of each to the mixed solution obtained in the first step and mix well; the third step is to thoroughly mix the mixed solution from the first step and the compounds added in the second step in the 96-well plate, transfer 22.5 μL to each well of a 384-well black plate, with 3 replicates per group. Incubate the 384-well black plate at room temperature in the dark for 15 min and read the values ​​using a microplate reader. The excitation and emission wavelengths are 495 nm and 520 nm, respectively. Use Graphpad Prism 8.0 software to plot the results. Figure 1 The 520 / 495 ratio curve. From... Figure 1 The data results show that all five FXR ligands have good activation activity.

[0050] Example 2: Pharmacological activity of farnesol X receptor clinical drugs against pulmonary fibrosis

[0051] Experimental Procedure: Primary lung fibroblasts were extracted from the lung tissue of 6-8 week old C57BL / 6 mice (Violentia Laboratory Animal Technology Co., Ltd.) and cultured in DMEMF12 medium (Gibco) containing 10% FBS. The primary lung fibroblasts were seeded into six-well plates. When the cells adhered and reached a density of 70%, TGF-β (Proteintech, Cat No. HZ-1011) at a final concentration of 10 ng / m³ was added to stimulate the transformation of fibroblasts into myofibroblasts. At this point, fibrosis-related genes were significantly upregulated, thus mimicking the occurrence of fibrosis at the cellular level. Experimental groups were set up as follows: a control group (containing the same concentration of DMSO as the compound group), a TGF-β group, and groups receiving TGF-β in combination with nine different FXR agonists. After culturing in a cell culture incubator for 48 hours, the cells were washed three times with sterile PBS, with the last wash removing any residual PBS. Cells were collected using 1 mL of trizol (Takara). 200 μL of chloroform was added to an EP tube, and the mixture was gently inverted 10-20 times to mix. The tube was incubated at room temperature for 5 min, at which point the solution separated into three layers (RNA on top, DNA in the middle, and organic solvent at the bottom). The mixture was centrifuged at 12000 rpm for 15 min at 4°C. 400 μL of the supernatant was then transferred to a new EP tube, and an equal volume of isopropanol was added. The mixture was inverted 10-20 times to mix, and the tube was incubated on ice for 10 min. The tube was then centrifuged at 12000 rpm for 10 min at 4°C. The supernatant was discarded, and the precipitate was washed with 1 mL of 75% ethanol. The precipitate was centrifuged at 12000 rpm for 5 min at 4°C. The supernatant was discarded, and the precipitate was dried at room temperature until it became clear. Depending on the amount of precipitate, an appropriate amount of RNase-free water was added to dissolve the precipitate. After mixing, the RNA concentration was measured.

[0052] 1 μg of total RNA was reverse transcribed into cDNA. The reaction solution was prepared according to the experimental procedures of the SYBR Green Pro Taq HS premixed qPCR kit from Acrylic Acid. Each sample was tested in triplicate. Ct values ​​were measured using the following method: Expression ratio = 2 - [(Target gene Ct in experimental group - Internal reference gene Ct in experimental group) - (Target gene Ct in control group - Internal reference gene Ct in control group)]. The primer sequences used in the experiment are shown in Table 2. The experimental results are as follows: Figure 2 As shown in this study, a series of compounds of the farnesoid X receptor all showed significant inhibitory effects on the transcriptional activity of fibrosis-related genes (FN-1, Col1a1, α-SMA), with the effects varying slightly depending on the type of compound.

[0053] Table 2. Primer Sequences

[0054]

[0055] Example 3: Pharmacological activity of farnesol X receptor clinical drugs against pulmonary fibrosis

[0056] Experimental Procedure: Primary lung fibroblasts were extracted from the lung tissue of 6-8 week old C57BL / 6 mice (Vitollife Laboratory Animal Technology Co., Ltd.) and cultured in DMEMF12 medium (Gibco) containing 10% FBS. The primary lung fibroblasts were seeded into six-well plates. When the cells adhered and reached a density of 70%, TGF-β (Proteintech, Cat No. HZ-1011) at a final concentration of 10 ng / m³ was added to stimulate the transformation of fibroblasts into myofibroblasts. At this point, fibrosis-related genes were significantly upregulated, thus mimicking the occurrence of fibrosis at the cellular level. Experimental groups included a control group (treated with the same concentration of DMSO as the compound group), a TGF-β group, and groups treated with TGF-β in combination with seven different FXR agonists. After culturing in a cell culture incubator for 48 hours, the cells were washed with sterile PBS, and RIPA lysis buffer (Proteintech, PR20035) was added, along with protease inhibitors (Selleck Chemicals) and phosphatase inhibitors (Selleck Chemicals). The cells were lysed on ice for 30 minutes, centrifuged at 12000 rpm for 10 minutes, and the supernatant was used for BCA quantification (Thermo Fisher). An appropriate amount of 5× loading buffer was added, and the cells were boiled at 95°C for 10 minutes. The resulting samples were then subjected to Western blot experiments. Results are as follows: Figure 3 As shown, a series of FXR compounds inhibited the protein expression of fibrosis-related genes to varying degrees. Specifically, these compounds significantly reduced the expression levels of key proteins closely related to the fibrosis process, including fibronectin-1 (FN-1), collagen α1 chain (Col1a1), and SMAD3 phosphorylation. This downregulation of protein expression suggests that the investigated compounds may slow or halt the progression of fibrosis by intervening in fibrosis-related signaling pathways. This finding provides important molecular mechanistic evidence for the development of novel anti-fibrosis therapies and lays an experimental foundation for future clinical applications.

[0057] Example 4: Evaluation of the pharmacological activity of a clinical compound targeting the farnesoid X receptor in inhibiting pulmonary fibrosis in mice.

[0058] Sufficient male C57 / BL6 mice aged 6-8 weeks were prepared. After respiratory anesthesia, 50 μL of bleomycin BLM (Selleck Chemicals) at 3 mg / kg was administered intratracheally. Bleomycin is a multi-component antibiotic composed of basic glycopeptides produced by Streptomyces verticillata that can induce pulmonary fibrosis. Starting the day after bleomycin treatment, seven compounds were continuously administered by gavage every morning for 21 days. These seven compounds included six FXR modifiers (TERN101, Cilofexor, PX20606, Nidufexor, Tropifexor, and Omesdafexor) and the yang-ginseng compound nintedanib, all dissolved in 0.5% sodium carboxymethyl cellulose (CMC-Na). The final drug concentrations were TERN101 (10 mg / kg), Cilofexor (30 mg / kg), PX20606 (10 mg / kg), Nidufexor (10 mg / kg), Tropifexor (1 mg / kg), Omesdafexor (10 mg / kg), and Nintedanib (10 mg / kg). After drug administration, mouse lung tissue was fixed in paraformaldehyde and stained with hematoxylin and eosin (HE) to assess pathological changes in the mouse lung tissue. The experimental flowchart is shown below. Figure 4 A. Experimental results are as follows Figure 4 As shown in Figure B, after nebulized bleomycin in the trachea, the alveolar walls of mice were significantly thickened, the lungs showed severe consolidation and collagen deposition, exhibiting symptoms of pulmonary fibrosis. After treatment with seven compounds, the lungs of the mice in the treatment group showed varying degrees of improvement, with lung morphology approaching normal, and the treatment effect was comparable to that of the Yangshen compound nintedanib.

[0059] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. Use of farnesol X receptor agonists in the preparation of medicaments or formulations for: (A1) prevention or treatment of fibrotic diseases; and / or, (A2) in vitro inhibition of fibroblast transformation into myofibroblasts.

2. The application according to claim 1, characterized in that, The farnesoid X receptor agonists include any one or more combinations of TERN101, Cilofexor, PX20606, Nidufexor, Tropifexor, EDP305, Omesdafexor, INT767, GW4064, or their precursors or pharmaceutically acceptable salts or derivatives.

3. The application according to claim 1, characterized in that, The drug or preparation is used for one or more of the following: (B1) In vitro inhibition of fibroblast transformation into myofibroblasts; (B2) Inhibits the expression of tissue fibrosis-related proteins; (B3) Inhibits tissue fibrosis-related signaling pathways; (B4) Improves symptoms of tissue fibrosis; (B5) Inhibits or improves inflammation caused by tissue fibrosis; (B6) Improve the survival rate of patients with tissue fibrosis; (B7) Prevention or treatment of tissue fibrosis.

4. The application according to claim 3, characterized in that, The tissue fibrosis-related proteins include one or more of the following: Fn-1, COLA1, and α-SMA; The inhibition of tissue fibrosis-related protein expression includes inhibiting the expression of tissue fibrosis-related proteins at both the transcriptional and translational levels.

5. The application according to claim 3, characterized in that, The tissue fibrosis-related signaling pathway is the TGF-β / SMAD signaling pathway.

6. The application according to claim 1, characterized in that, The farnesol X receptor agonists include tablets, capsules, solutions, granules, pills, powders, ointments, pills, suspensions, powders, injections, suppositories, creams, sprays, or patches.

7. The application according to claim 1, characterized in that, The farnesoid X receptor agonist is administered via intramuscular injection, intranasal, intratracheal, gastric, rectal, mucosal presentation, intravenous delivery, or intradermal or subcutaneous administration.

8. The application according to claim 1, characterized in that, The fibrosis includes one or more of the following: renal fibrosis, pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, bone marrow fibrosis, adipose tissue fibrosis, pancreatic fibrosis, retroperitoneal fibrosis, mesenteric fibrosis, breast fibrosis, cystic fibrosis, gastrointestinal tract fibrosis, or skin fibrosis. Preferably, the fibrosis is pulmonary fibrosis, and more preferably, idiopathic pulmonary fibrosis.

9. The application according to claim 8, characterized in that, The symptoms of pulmonary fibrosis include one or more of the following: collagen deposition in the lungs, pulmonary scarring, organ parenchyma, and thickening of the alveolar walls.

10. A method for inhibiting the transdifferentiation of lung fibroblasts into myofibroblasts in vitro, characterized in that, The procedure includes contacting the lung fibroblasts with a therapeutically effective amount of the farnesol X receptor agonist.

Images