Application of beta-elemonic acid or derivative thereof in preparation of medicine for regulating cell senescence and preventing and / or treating senescence-related diseases

Abstract

The invention belongs to the technical field of biological medicines, and discloses application of beta-elemonic acid or a derivative or pharmaceutically acceptable salt thereof in preparation of medicines for regulating cell senescence and preventing and / or treating senescence-related diseases, including application as a cell senescence regulator (especially a senescence cell scavenger), and application of beta-elemonic acid or a derivative or pharmaceutically acceptable salt thereof in preparation of medicines for regulating cell senescence and preventing and / or treating senescence-related diseases. The invention also relates to application of the compound in preparation of medicines for preventing and / or treating diseases (such as organ fibrosis diseases and metabolic diseases) driven by cell aging pathology. In-vivo and in-vitro experiments prove that beta-EA can significantly reduce the number of SA-beta-gal positive senescence cells and down-regulate the expression of a core senescence marker protein p21 no matter in an in-vitro cell model or in an in-vivo pathological tissue. The invention also proves that beta-EA can reverse the degree of cell fibrosis, inhibits the transcriptional activity of an epithelial-mesenchymal transition pathway, has remarkable anti-fibrosis activity, and can be applied to treatment of organ fibrosis and other senescence-driven diseases.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and specifically relates to the use of β-elemene acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs for regulating cellular senescence and preventing and / or treating senescence-related diseases, including its use as a cellular senescence regulator (especially a senescent cell scavenger), and its use in the preparation of drugs for the prevention and / or treatment of diseases pathologically driven by cellular senescence (such as organ fibrosis and metabolic diseases). Background Technology

[0002] Cellular senescence refers to an irreversible state of cell cycle arrest that cells enter after being subjected to various stressors (such as oxidative stress, DNA damage, metabolic load, etc.). Although cellular senescence plays a certain physiological role in embryonic development and wound healing, increasing research confirms that in chronic disease states, the pathological accumulation of senescent cells in lesion tissues is a key driver of disease progression.

[0003] These retained senescent cells, while no longer proliferating, remain metabolically active and continuously secrete a series of pro-inflammatory factors, chemokines, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP). SASP leads to chronic inflammation in the microenvironment, induces secondary senescence in neighboring normal cells, and abnormally activates the epithelial-mesenchymal transition (EMT) process, resulting in excessive fibroblast activation and collagen deposition, ultimately causing tissue damage and organ fibrosis. Currently, it is scientifically accepted that cellular senescence is the common pathological basis for many chronic diseases, including metabolic diseases (such as polycystic ovary syndrome (PCOS) and metabolic-associated fatty liver disease (MAFLD / MASH)) and various organ fibrosis diseases (such as liver, lung, and kidney fibrosis). Currently, strategies targeting the elimination of pathologically senescent cells (i.e., senolytics therapy) have become a research hotspot. However, some existing drug candidates (such as certain BCL-2 family inhibitors) have shown significant toxic side effects (such as thrombocytopenia) in preclinical or clinical studies, limiting their clinical translation. Therefore, there is an urgent clinical need to develop novel drugs with unique mechanisms of action that are safe and effective in regulating and reducing the burden of pathological cellular senescence.

[0004] β-elemeneic acid is a natural tetracyclic triterpenoid compound found in plants such as frankincense. Existing technologies have reported its anti-inflammatory, antitumor, or potential metabolic regulatory activities. However, these existing research perspectives are limited to improving single symptoms or isolated phenotypes downstream of diseases (e.g., simply inhibiting the expression of certain inflammatory mediators or regulating individual metabolic indicators). Summary of the Invention

[0005] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide the use of β-elemene acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs for regulating cellular senescence and preventing and / or treating aging-related diseases.

[0006] Based on the core driving role of cellular senescence in chronic diseases, this invention provides β-elemene acid or its derivatives or pharmaceutically acceptable salts to eliminate pathological senescent cells at the source, providing effective support for the prevention and / or treatment of aging-related diseases and opening up a new application direction for tetracyclic triterpenoids in the pharmaceutical field.

[0007] The present invention also provides the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts as a regulator of cell senescence.

[0008] The present invention also provides the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of medicaments for reducing the cellular burden of senescent tissues or inhibiting the senescence-associated secretory phenotype (SASP).

[0009] The present invention also provides the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of chronic diseases (particularly organ fibrosis and complex metabolic diseases) driven or associated with pathological accumulation of senescent cells.

[0010] The objective of this invention is achieved through the following solution:

[0011] The use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of one of the following drugs: (a) Regulating cellular senescence; (ii) Prevention and / or treatment of age-related diseases; (iii) Anti-organ fibrosis.

[0012] Furthermore, the structural formula of the β-elemene acid is shown below: .

[0013] Furthermore, the effect of regulating cellular senescence specifically includes, but is not limited to, one or more of the following: (1) Reduce the burden on senescent cells: significantly reduce the number or area of ​​cells or regions that are positive for senescence-related β-galactosidase (SA-β-gal) staining in tissues or cells; (2) Downregulate core markers of aging: inhibit the expression levels of key proteins in cell cycle arrest (such as p21); (3) Blocking the senescence transcriptional program: significantly downregulating the enrichment of cellular senescence-related pathways (such as the FRIDMAN_SENESCENCE_UP gene set) at the transcriptome level; (4) Inhibit pathological remodeling mediated by aging-associated secretory phenotype (SASP): By clearing senescent cells, downstream epithelial-mesenchymal transition (EMT) and collagen fiber deposition are blocked.

[0014] Furthermore, the age-related diseases are preferably tissue remodeling or fibrosis diseases caused by the accumulation of senescent cells, including but not limited to: (1) Organ fibrosis diseases: such as reproductive system fibrosis (e.g., ovarian fibrosis), digestive system fibrosis (e.g., MASH-related liver fibrosis), pulmonary fibrosis, or renal fibrosis; (2) Age-related metabolic diseases: such as polycystic ovary syndrome (PCOS) and metabolic-associated fatty liver disease (MASH / MAFLD).

[0015] Furthermore, the use of β-elemene acid or its derivatives or pharmaceutically acceptable salts as regulators of cellular senescence includes the manufacture of agents for the removal of senescent cells from an organism and the selective induction of cell death in senescent cells.

[0016] Furthermore, the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs that reduce the burden of senescent cells in lesion tissues or inhibit the senescence-associated secretory phenotype (SASP).

[0017] Furthermore, the use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of chronic diseases (particularly organ fibrosis and complex metabolic diseases) driven or associated with the pathological accumulation of senescent cells.

[0018] Furthermore, the same or different drugs include therapeutically effective amounts of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts.

[0019] Furthermore, the same or different drugs can be prepared into various pharmaceutical dosage forms using conventional methods. These dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, powders, pills, elixirs, suspensions, tinctures, drops, and other oral dosage forms, as well as injections and other non-oral dosage forms, such as injections.

[0020] Furthermore, the drugs, whether identical or different, may also contain one or more pharmaceutically acceptable carriers or excipients.

[0021] Furthermore, the carrier or excipient may include diluents, adhesives, surfactants, humectants, adsorbents, lubricants, fillers, disintegrants, preservatives, etc.

[0022] The present invention also provides a pharmaceutical composition for the prevention and / or treatment of age-related diseases, comprising the β-elemene acid or a derivative thereof or a pharmaceutically acceptable salt thereof.

[0023] Compared with the prior art, the present invention has the following significant advantages:

[0024] (1) Unlike existing technologies that only treat downstream inflammation or metabolic indicators, the tetracyclic triterpenoids (such as β-elemeneic acid, β-EA) provided by this invention can specifically reduce the burden of senescent cells in lesion tissues. Multidimensional in vitro and in vivo experimental data consistently confirm that, regardless of the in vitro cell model ( Figure 1 ), or in the pathological tissues within the body ( Figure 3 Both β-EA significantly reduced the number of SA-β-gal positive senescent cells and downregulated the expression of the core senescence marker protein p21. Figure 2 This "burden reduction" effect at the source cuts off the driving force of pathological progression, providing effective support for the prevention and / or treatment of age-related diseases.

[0025] (2) This invention pioneers a new cross-organ universal treatment model of "clearing senescent cells and blocking fibrosis": Through head-to-head verification using dual disease models (PCOS ovarian model + MASH liver model), this invention reveals the broad spectrum and universality of the β-EA mechanism. At the phenotypic level: with the clearance of senescent cells, collagen deposition in PCOS ovarian tissue (Sirius red staining) is significantly reduced, and the degree of fibrosis is reversed. Figure 4 At the mechanistic level: GSEA analysis of the liver transcriptome further confirmed that β-EA, while significantly downregulating the senescence pathway, simultaneously inhibited the transcriptional activity of the epithelial-mesenchymal transition (EMT / Fibrosis) pathway. Figure 5 , Figure 6 This pharmacological property of "upstream scavenging of aging and downstream spontaneous reversal of fibrosis" has been validated in both reproductive and metabolic systems, demonstrating its enormous clinical translational potential as an anti-aging-driven fibrosis drug.

[0026] (3) Safety advantages: As a natural active ingredient derived from medicinal and edible plants, β-EA shows better safety and drug development prospects compared to some synthetic senescent cell scavengers known to have serious side effects (such as thrombocytopenia), and therefore has broad application prospects. Attached Figure Description

[0027] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 This invention demonstrates the ameliorative effect of compound β-EA on an androgen + H2O2-induced cell senescence model (in vitro SA-β-gal staining). A: Representative photographs of SA-β-gal staining in each group (blue indicates senescent cells); B: Quantitative statistical graph of the proportion of SA-β-gal positive cells.

[0029] Figure 2 This image shows the effect of compound β-EA of the present invention on the expression of p21 protein, a marker of cellular senescence induced by androgen + H2O2 (in vitro Western Blot). A: Western Blot electrophoresis bands of p21 protein in each group of cells; B: Gray-scale analysis statistical graph of the relative expression level of p21 protein.

[0030] Figure 3 This invention demonstrates the effect of compound β-EA in clearing senescent cells from ovarian tissue in a PCOS rat model (in vivo SA-β-gal staining). A: Representative photographs of frozen sections of ovarian tissue from each group stained with SA-β-gal; B: Quantitative statistical graph of SA-β-gal positive areas in ovarian tissue.

[0031] Figure 4 This invention demonstrates the effect of compound β-EA in improving ovarian tissue fibrosis in a PCOS rat model (in vivo Sirius red staining). A: Representative photographs of Sirius red staining of ovarian tissue from each group of rats (red represents collagen fibers); B: Quantitative statistical graph of collagen fiber-positive areas.

[0032] Figure 5 This invention demonstrates the regulatory effect of compound β-EA on the cellular senescence pathway at the transcriptome level in liver tissue of MASH mice. The GSEA enrichment analysis plot shows changes in the "Cellular Senescence" pathway.

[0033] Figure 6 This invention demonstrates the regulatory effect of compound β-EA on the fibrosis pathway at the transcriptomic level in the liver tissue of MASH mice. The GSEA enrichment analysis plot shows "Fibrosis".

[0034] Statistical differences are marked with * in the figure. p <0.05,** p<0.01, *** p <0.001 vs. blank group; # p <0.05, ## p <0.01, ### p <0.001 vs model group. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, all materials involved in the following embodiments are commercially available. Unless otherwise specified, all methods described are conventional methods.

[0036] In one embodiment, β-elemeneic acid or its derivatives or pharmaceutically acceptable salts thereof are used in the preparation of one of the following pharmaceuticals: (a) Regulating cellular senescence; (ii) Prevention and / or treatment of age-related diseases; (iii) Anti-organ fibrosis.

[0037] In specific embodiments of the present invention, the drugs, whether identical or different, include therapeutically effective amounts of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts thereof.

[0038] In another embodiment, a pharmaceutical composition for the prevention and / or treatment of aging-related diseases comprises the aforementioned β-elemeneic acid or a derivative thereof or a pharmaceutically acceptable thereof.

[0039] In specific embodiments of the present invention, the dosage of the drug or drug composition of the present invention can be varied according to factors such as formulation method, manner, patient's age, weight, gender, condition, diet, time, route, excretion rate, and responsiveness.

[0040] In specific embodiments of the present invention, the therapeutically effective amount refers to an amount that can produce a therapeutic effect on humans and / or animals and is acceptable to humans and / or animals. For example, a therapeutically or pharmaceutically effective amount refers to the amount of drug required to produce the desired therapeutic effect, which can be reflected by the results of clinical trials, animal model studies, and / or in vitro studies. A pharmaceutically effective amount depends on several factors, including but not limited to: the characteristics of the treatment subject (such as the height, weight, sex, age, and medication history of the treatment subject), and the severity of the disease.

[0041] In specific embodiments of the present invention, the administration methods of the drug or drug composition include, but are not limited to: oral administration, non-gastrointestinal administration, administration via inhalation spray, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, or administration via an implanted drug storage device. Oral administration or injection is preferred.

[0042] In specific embodiments of the present invention, any orally acceptable dosage form may be used, including but not limited to capsules (hard capsules, soft capsules), tablets (sugar-coated tablets, film-coated tablets, enteric-coated tablets), aqueous suspensions, or solutions.

[0043] In specific embodiments of the present invention, liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.

[0044] In specific embodiments of the present invention, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0045] In specific embodiments of the invention, the drug or pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients. The pharmaceutically acceptable carriers or excipients may contain inert components that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carriers or excipients should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or free from other undesirable reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

[0046] In specific embodiments of the invention, pharmaceutically acceptable carriers or excipients include, but are not limited to, diluents, binders, surfactants, humectants, adsorbents, lubricants, fillers, disintegrants, preservatives, etc. These substances are used as needed to aid in the stability of the formulation or to contribute to its activity or bioavailability, or to produce an acceptable taste or odor when taken orally. Formulations that can be used in such pharmaceutical compositions may be in the form of the original compound itself or optionally in the form of its pharmaceutically acceptable salts. Such formulated pharmaceutical compositions may be administered in any suitable manner known to those skilled in the art as needed.

[0047] In specific embodiments of the present invention, the diluent includes, but is not limited to, lactose, sodium chloride, glucose, urea, starch, and water.

[0048] In specific embodiments of the present invention, the adhesive includes, but is not limited to, starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, alginate and alginates, xanthan gum, hydroxypropylcellulose and hydroxypropylmethylcellulose.

[0049] In specific embodiments of the present invention, the surfactants include, but are not limited to, polyethylene oxide sorbitan fatty acid ester, sodium lauryl sulfate, glyceryl monostearate, and hexadecyl alcohol.

[0050] In specific embodiments of the present invention, the humectant includes, but is not limited to, glycerin and starch.

[0051] In specific embodiments of the present invention, the adsorption carrier includes, but is not limited to, starch, lactose, bentonite, silica gel, kaolin, and bentonite.

[0052] In specific embodiments of the present invention, the lubricant includes, but is not limited to, zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearate fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium dodecyl sulfate.

[0053] In specific embodiments of the present invention, the fillers include, but are not limited to, mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polysaccharides, coupled sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, kelp polysaccharide powder, agar powder, calcium carbonate, and sodium bicarbonate.

[0054] In specific embodiments of the present invention, the disintegrants include, but are not limited to, crosylvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylmethyl, crosylcarboxymethyl cellulose sodium, and soybean polysaccharides. Example 1

[0055] Evaluation of the in vitro activity of compound β-EA in scavenging senescent cells and downregulating aging markers.

[0056] (1) Experimental procedure:

[0057] Human ovarian granulosa cell line (KGN) was used. To simulate the pathological oxidative stress state under the hyperandrogenic environment of PCOS, this invention established a unique dual-stimulation senescence model. Specifically, cells were first pretreated with a hyperandrogenic medium (containing 200 nM dihydrotestosterone (DHT)) for 24 hours, followed by co-treatment with a subcytotoxic concentration of H2O2 (100 nM) for 2 hours to induce a pathological premature senescence state (model group). Preliminary experiments showed that neither androgens nor H2O2 alone could effectively induce a significant SA-β-gal positive senescence phenotype, while the dual combined stimulation significantly induced cellular senescence.

[0058] Subsequently, cells were treated with different concentrations of β-EA (e.g., 1 μM, 2 μM, 4 μM) for 24 hours (treatment group). Normally cultured cells served as the control group.

[0059] Cellular senescence was detected using the SA-β-gal staining kit; blue-stained cells were senescent cells. The expression level of p21, a core marker of senescence, was detected using Western blotting.

[0060] (2) Analysis of experimental results:

[0061] like Figure 1 As shown, after DHT+H2O2 induction, the proportion of SA-β-gal-positive blue cells in the model group increased significantly, indicating that the cells successfully entered a senescent state. Compared with the model group, the number of blue senescent cells in the culture dish of the β-EA-treated group was significantly reduced in a dose-dependent manner.

[0062] like Figure 2 Western blot results showed that DHT+H2O2 induction significantly upregulated p21 protein expression in the model group cells. Treatment with β-EA significantly inhibited p21 protein expression.

[0063] Conclusion: In vitro experimental results demonstrate that the compound β-EA of this invention can significantly reduce the senescent cell load under stress and downregulate the key senescence marker p21, showing potent cellular senescence regulatory activity. Example 2

[0064] The synergistic effect of compound β-EA of the present invention in clearing pathological senescent cells and improving ovarian fibrosis in an in vivo PCOS model.

[0065] (1) Experimental procedure:

[0066] Sprague Dawley rats, housed in the clean-grade laboratory animal facility of Guangzhou Medical University, were used to establish the PCOS model. Four-week-old female rats were subcutaneously injected with DHEA (60 mg / kg body weight) daily for 28 consecutive days. Successful PCOS model establishment was assessed by detecting serum testosterone levels, estrous cycles, H&E staining of the ovaries, and the number of mature follicles. The experiment consisted of a normal control group (Control), a model group (PCOS), a low-dose β-EA group (10 mg / kg), and a high-dose β-EA group (20 mg / kg); five rats were used in each group. After successful model establishment, the Vehicle and PCOS groups were administered an equal volume of PEG300 by gavage daily, while the low-dose and high-dose β-EA groups were administered the corresponding doses (dissolved in 0.2 mL of PEG300) by gavage daily for 28 days.

[0067] After sampling, frozen sections of ovarian tissue were prepared for SA-β-gal staining; paraffin sections were prepared for p21 immunohistochemical staining and Sirius Red collagen staining.

[0068] (2) Analysis of experimental results:

[0069] ① Direct evidence of the body's clearance of senescent cells: such as Figure 3 As shown, numerous scattered SA-β-gal positive blue staining areas appeared in the ovarian tissue (especially the stromal region) of the PCOS model group, indicating severe cellular senescence accumulation in the ovarian tissue under pathological conditions. After β-EA treatment, the blue positive signal in the ovarian tissue was significantly reduced.

[0070] ② Evidence linking improvement in tissue fibrosis: such as Figure 4 As shown, Sirius red staining revealed significant red collagen fiber deposition (fibrosis) in the ovarian stroma and perivascular area of ​​the PCOS model group. In the same batch of animals, with the clearance of senescent cells by β-EA (see...),... Figure 3 It can be observed that the red collagen deposition area in the ovarian tissue of the β-EA group is also significantly reduced, and the degree of fibrosis is improved.

[0071] Conclusion: In vivo experiments confirmed that β-EA can clear senescent cells accumulated in the ovaries under PCOS pathological conditions. More importantly, this anti-aging effect and the efficacy in improving ovarian fibrosis showed a high degree of correlation in time and space, strongly supporting the mechanism hypothesis that "clearing senescent cells is the fundamental reason for improving downstream tissue fibrosis." Example 3

[0072] Validation of the cross-organ anti-aging and anti-fibrotic mechanism of compound β-EA in the MASH liver fibrosis model.

[0073] (1) Experimental procedure:

[0074] To verify the universality of β-EA's cellular senescence-regulating mechanism in different organs, this experiment used a classic metabolic-associated steatohepatitis (MASH) mouse model. Six- to eight-week-old male C57BL / KsJ-db / db spontaneously diabetic mice were selected and fed a high-fat, high-fructose Western diet (WD) for 12 weeks to induce severe hepatic steatosis, inflammation, and fibrosis (model group). Age-matched db / m mice were fed a standard diet as a normal control group (WT). After successful modeling, C57BL / KsJ-db / db mice were randomly assigned to groups. The beta-EA group received daily gavage administration of β-EA (20 mg / kg, dissolved in solvent), while the model group and the normal control group (WT) received an equal volume of solvent daily gavage. After 8 weeks of continuous administration, tissue samples were collected. Fresh liver tissue was collected, total RNA was extracted, and Illumina high-throughput transcriptome sequencing (RNA-seq) was performed. Based on sequencing data, we used GSEA (Gene Set Enrichment Analysis) software to perform targeted enrichment analysis on the gene set related to "Cellular Senescence" (FRIDMAN_SENESCENCE_UP) and the core pathway of "Epithelial-Mesenchymal Transition / Fibrosis" (HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION), and calculated the normalized enrichment score (NES) to assess changes in pathway activity.

[0075] (2) Results analysis:

[0076] ① Unique aging-clearing effect:

[0077] like Figure 5 As shown, GSEA analysis revealed dynamic changes in senescence signals in liver tissue. Compared to the WT control group, the “FRIDMAN_SENESCENCE_UP” senescence gene set showed significant positive enrichment in the MASH model group, indicating a large accumulation of senescent cells in the liver under pathological conditions. However, after β-EA treatment, the enrichment fraction (NES) of this senescence gene set was significantly reversed (NES < 0), showing a significant downregulation trend. This transcriptomic evidence is highly consistent with the reduced SA-β-gal staining observed in the PCOS ovary model in Example 2, confirming that β-EA also has the activity of clearing senescent cells in the liver.

[0078] ②Significant anti-fibrotic effect:

[0079] like Figure 6As shown, analysis of the core mechanisms of fibrosis revealed that the Epithelial Mesenchymal Transition (EMT) pathway was highly activated (significantly positively enriched) in the liver of the MASH model group, indicating severe tissue remodeling and the initiation of fibrosis. After β-EA intervention, the transcriptional activity of the EMT pathway was significantly inhibited (NES < 0, significantly negatively enriched). This indicates that β-EA can directly block the progression of liver fibrosis at the gene transcription level.

[0080] (3) Conclusion:

[0081] This embodiment, through transorgan (liver) transcriptomic analysis, confirms that β-EA does not only act on the reproductive system, but exerts a broad-spectrum anti-fibrotic effect through the core axis of "clearing senescent cells-blocking EMT process." This discovery strongly supports the great potential of the compounds of this invention in the treatment of age-driven organ fibrosis.

[0082] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of one of the following drugs: (a) Regulating cellular senescence; (ii) Prevention and / or treatment of age-related diseases; (iii) Anti-organ fibrosis.

2. The application according to claim 1, characterized in that... The structural formula of the β-elemene acid is shown below: 。 3. The application according to claim 1, characterized in that... The use of β-elemene acid or its derivatives or pharmaceutically acceptable salts as regulators of cellular senescence.

4. The application according to claim 1, characterized in that... The use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of drugs that reduce the burden of senescent cells in lesion tissues or inhibit senescence-related secretory phenotypes.

5. The application according to claim 1, characterized in that... The use of β-elemeneic acid or its derivatives or pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of chronic diseases driven by or associated with the pathological accumulation of senescent cells.

6. The application according to claim 1, characterized in that: The age-related diseases are those caused by the accumulation of senescent cells, resulting in tissue remodeling or fibrosis, including organ fibrosis or age-related metabolic diseases.

7. The application according to claim 6, characterized in that: The organ fibrosis diseases include reproductive system fibrosis, digestive system fibrosis, pulmonary fibrosis, or renal fibrosis; the age-related metabolic diseases include polycystic ovary syndrome and metabolic-related fatty liver disease.

8. The application according to claim 1, characterized in that... The drug comprises a therapeutically effective amount of β-elemeneic acid or a derivative thereof or a pharmaceutically acceptable salt thereof.

9. The application according to claim 1, characterized in that... The drugs are manufactured into various dosage forms using conventional methods, including: tablets, capsules, oral liquids, lozenges, granules, pills, elixirs, suspensions, tinctures, drops, and injections for oral administration.

10. The application according to claim 1, characterized in that: The drug also contains one or more pharmaceutically acceptable carriers or excipients.

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