Application of diosgenin in preparation of medicine for treating heart failure

Abstract

The invention provides an application of diosgenin in preparation of a medicine for treating heart failure. In-vivo and in-vitro experiments prove that the diosgenin can be directly combined with heat shock protein HSP90 in a targeting manner, and can be used for effectively relieving myocardial hypertrophy caused by pressure load, inhibiting cardiac fibrosis and finally delaying the progress of heart failure by activating an HSP90 / LKB1 / AMPK signal axis, maintaining the mitochondrial function of myocardial cells and improving fatty acid metabolism for the first time. The discovery provides a new drug choice and a clear action target for the treatment of heart failure.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of small molecule drugs, and particularly relates to application of diosgenin in preparation of a medicine for treating heart failure. BACKGROUND

[0002] Heart failure is a complex clinical syndrome and the terminal stage and adverse consequence of most cardiovascular diseases. It is characterized by high mortality and poor prognosis, and brings heavy burden to society and individuals. Therefore, early detection and treatment of heart failure related basic heart diseases have extremely important positive significance for delaying disease progression, improving patient quality of life and reducing heart failure mortality.

[0003] In the pathological development process of heart failure, cardiac hypertrophy is a key intermediate link. Cardiac hypertrophy is an adaptive and compensatory mechanism of the heart in response to various long-term physiological and pathological stimuli (such as hypertension, aortic valve stenosis, etc.), mainly maintaining cardiac output by increasing the contractility of cardiomyocytes. However, continuous pathological stimulation can induce chronic myocardial hypertrophy, and this compensatory mechanism will eventually be decompensated, leading to deterioration of cardiac function and progression to heart failure. From the cellular composition, the heart contains multiple types of cells, mainly including cardiomyocytes, fibroblasts, vascular smooth muscle cells, endothelial cells and immune cells, etc. Among them, cardiomyocytes account for about 30% of the total number of cells in the heart, but their mass accounts for 70%-80% of the total mass of the heart. Since most cardiomyocytes cannot divide and proliferate after adulthood, the heart mainly relies on changing its own size and shape, adjusting gene expression patterns, and remodeling cytoskeleton and extracellular matrix to increase the volume and mass of the whole heart to adapt to the increased workload when coping with the load.

[0004] According to the nature of the stimulus, cardiac hypertrophy can be divided into physiological hypertrophy and pathological hypertrophy. Physiological cardiac hypertrophy usually occurs in athletes who engage in endurance training for a long time or pregnant women, and is characterized by normal or even enhanced cardiac contractile function, orderly remodeling of cardiac structure and tissue, and the hypertrophy is completely reversible and does not progress to heart failure. For example, weight lifting training mainly causes pressure overload, leading to concentric physiological hypertrophy; while swimming and running mainly cause volume overload, leading to eccentric physiological hypertrophy. In contrast, pathological cardiac hypertrophy is induced by pathological factors such as hypertension stress, aortic stenosis, myocardial infarction, excessive activation of neural and humoral factors or genetic cardiomyopathy. Its core feature is the progressive decline of cardiac systolic and diastolic function, often accompanied by myocardial cell death and interstitial fibrosis, and eventually irreversibly progresses to heart failure.

[0005] Currently, although treatments for heart failure are constantly evolving, challenges remain, particularly in intervening in early myocardial hypertrophy and delaying or even reversing the progression of heart failure. There is an urgent need to develop new effective drugs and therapeutic targets.

[0006] Diosgenin (Dio) is a naturally occurring steroidal saponin widely distributed in plants of the Dioscoreaceae and Trigonella families, and also found in various plants of the Liliaceae, Zingiberaceae, and Solanaceae families. Within plants, diosgenin typically exists as dioscin, bound to glycosyl groups (such as glucose or rhamnose). Industrially, diosgenin is usually obtained by hydrolyzing diosgenin, while microbial conversion methods are gaining increasing attention due to their high specificity and low environmental pollution.

[0007] Numerous preclinical and clinical studies have revealed that diosgenin possesses diverse and significant biological activities, demonstrating potential in the treatment of various diseases. Its pharmacological effects are broad, including but not limited to anticancer activity, cardiovascular protection, lipid-lowering effects, anti-inflammation, neuroprotection, apoptosis promotion, cell cycle arrest, and protective properties against multiple organs such as the stomach, skin, and liver. Many scientific studies have also confirmed the positive effects of diosgenin in the treatment of cardiovascular diseases, diabetes, hyperlipidemia, metabolic syndrome, and non-alcoholic fatty liver disease. Furthermore, some clinical observations have shown improvements in cognitive function, menopausal symptoms, and embryo quality in patients taking diosgenin.

[0008] Although the cardiovascular protective effects of diosgenin have been preliminarily recognized, its specific role in stress-induced cardiac hypertrophy and heart failure, as well as its underlying molecular mechanisms, particularly whether it exerts its cardioprotective effect through specific binding to key target proteins, remain unclear. Exploring the precise molecular targets and signaling pathways of diosgenin in combating heart failure is of significant scientific and clinical value for developing it into a novel and highly effective anti-heart failure drug and for providing new therapeutic strategies in this field. Summary of the Invention

[0009] The purpose of this invention is to provide a novel pharmaceutical use of diosgenin, namely its application in the preparation of drugs for treating heart failure. Specifically, this invention relates to a novel mechanism and use of diosgenin in preventing and alleviating stress-induced cardiac hypertrophy by targeting heat shock protein 90 (HSP90), thereby treating heart failure.

[0010] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies. Heart failure is an unfavorable endpoint in the development of various cardiovascular diseases, with high mortality and poor prognosis. Although diosgenin is known to have broad cardiovascular protective activity, its specific role and molecular mechanism in heart failure, particularly in intervening in the early pathological hypertrophic process of the heart, remain unclear. Therefore, there is currently a lack of effective anti-heart failure drugs based on the aforementioned well-defined mechanisms. This invention aims to provide a method for treating heart failure using diosgenin through specific targets, offering a new therapeutic strategy and drug candidate for this field.

[0011] To achieve the above objectives, the present invention proposes the use of diosgenin in the preparation of a medicament for treating heart failure.

[0012] Furthermore, the heart failure is heart failure caused by or related to stress overload.

[0013] Furthermore, the heart failure caused by the pressure load is due to the progression of cardiac hypertrophy; preferably, the diosgenin is used to alleviate or reverse myocardial hypertrophy.

[0014] Furthermore, the diosgenin exerts its effect by targeting HSP90.

[0015] Furthermore, the diosgenin directly binds to HSP90 and stabilizes the HSP90 protein.

[0016] Furthermore, the diosgenin exerts its anti-heart failure effect by activating the HSP90 / LKB1 / AMPK signaling axis, maintaining mitochondrial function in cardiomyocytes, and / or enhancing fatty acid metabolism.

[0017] The present invention also provides the use of a pharmaceutical composition in the preparation of a medicament for treating heart failure, said pharmaceutical composition comprising a therapeutically effective amount of diosgenin and a pharmaceutically acceptable carrier.

[0018] Further, the dosage of the pharmaceutical composition is 1 mg to 200 mg of diosgenin per kilogram of body weight per day; preferably, the dosage is 50 mg to 100 mg of diosgenin per kilogram of body weight per day; more preferably, the dosage is 75 mg of diosgenin per kilogram of body weight per day.

[0019] Furthermore, the dosage form of the pharmaceutical composition is an oral dosage form; preferably, the oral dosage form is a tablet, capsule, granule, or oral liquid.

[0020] The present invention also provides a pharmaceutical composition for treating heart failure, comprising: (i) A therapeutically effective amount of diosgenin is used as the active ingredient; (ii) pharmaceutically acceptable carriers; and, (iii) Optionally, excipients for enhancing solubility, said excipients including one or more of ethanol, polyethylene glycol and Tween-80.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention clarifies for the first time the novel use of diosgenin in treating heart failure by directly targeting HSP90, and elucidates its mechanism of action in maintaining myocardial energy metabolism homeostasis by regulating the HSP90 / LKB1 / AMPK signaling axis, breaking through the limitations of the original pharmacological understanding of this compound.

[0022] Diosgenin exhibits a multi-stage intervention capability in the progression of heart failure, simultaneously alleviating myocardial hypertrophy and cardiac fibrosis, achieving a comprehensive protective effect from early intervention to late inhibition.

[0023] Furthermore, this natural compound has no effect on normal cardiac function at effective therapeutic doses, demonstrating good safety and providing a significant advantage for its clinical translation. Attached Figure Description

[0024] Figure 1 This describes the mouse modeling and drug administration process for hypertrophic myocardial infarction.

[0025] Figure 2 This is Dio's relief of pressure-induced myocardial hypertrophy. A shows newly acquired ultrasound images of mice in each group; B shows statistical histograms of left ventricular ejection fraction and short-axis contractility; C shows HE staining of the heart; D shows WGA staining of the heart; E shows statistical histograms of cardiomyocyte area; F shows changes in the expression of marker genes related to myocardial hypertrophy; G shows changes in the expression of marker proteins related to myocardial hypertrophy; and H shows statistical histograms of protein expression changes.

[0026] Figure 3 This describes the mouse modeling process for heart failure and the drug administration procedure.

[0027] Figure 4 Dio alleviates heart failure caused by stress load. A shows newly acquired ultrasound images of mice in each group; B shows statistical histograms of left ventricular ejection fraction and short-axis contractile rate; C shows HE staining of the heart; D shows WGA staining of the heart and statistical histograms of cardiomyocyte area; E shows Masson staining and statistical histograms of myocardial fibrosis area; F shows changes in the expression of marker genes related to myocardial hypertrophy; and G shows changes in the expression of marker proteins related to myocardial hypertrophy and statistical histograms of protein expression changes.

[0028] Figure 5This is the detection of the Dio target. A is a schematic diagram of small molecule biotin pull-down combined with LC-MS to find potential Dio binding proteins, and B is the main protein interacting with HSP90 in the Bio-Dio pull-down protein peptide mass spectrometry analysis.

[0029] Figure 6 This is the verification result of the binding of diosgenin to HSP90 protein. A shows the binding of diosgenin to HSP90 protein from different sources detected by small molecule biotin pull-down assay, and B is the sensor diagram of the direct interaction between diosgenin and HSP90 protein detected by SPR.

[0030] Figure 7 This describes the modeling and administration process for HSP90 protein-degraded mouse myocardial hypertrophy.

[0031] Figure 8 Dio exerts its effects in the heart through HSP90. A is a HE staining image of the heart, B is a newly acquired ultrasound image of each group of mice, C is a WGA staining image of the heart, D is a histogram of left ventricular ejection fraction and short-axis contractility, and E is a histogram of cardiomyocyte area. Detailed Implementation

[0032] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0033] All raw materials used in this invention are not particularly limited in their source; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0034] There are no particular restrictions on the purity of any of the raw materials used in this invention. However, this invention preferably uses raw materials of analytical grade or purity commonly used in the field of chemical synthesis.

[0035] Example 1: Diosgenin relieves myocardial hypertrophy caused by stress overload 1. Laboratory animals and model construction To verify the alleviating effect of diosgenin (Dio) on stress-induced myocardial hypertrophy, healthy 8-week-old C57 / BL6 male mice (purchased from Shanghai Slack Animal Center) were used in the experiment. All mice were housed in an SPF-grade environment at the Tongji University Experimental Animal Center, with free access to food and water. All animal experimental procedures were reviewed and approved by the Tongji University Experimental Animal Ethics Committee.

[0036] The mouse pressure overload model was established through a transverse aortic constriction (TAC) surgery. In short, after anesthetizing mice, the aortic arch was dissected via thoracotomy, and ligated using 7-0 sutures around a 27G needle. The needle was then quickly withdrawn, causing partial stenosis of the aortic arch, thus establishing a cardiac pressure overload model. Mice in the sham group underwent only thoracotomy and aortic dissection, without ligation.

[0037] 2. Experimental grouping and drug administration Mice undergoing TAC surgery were randomly divided into two groups: the TAC + solvent group (Vehicle) and the TAC + Dio administration group (Dio), with n ≥ 5 mice in each group. The sham-operated group (Sham) served as a normal control.

[0038] The preparation method for the drug in the treatment group was as follows: One day before gavage, 30 mg of diosgenin (Dio) was accurately weighed and dissolved in 100 μL of anhydrous ethanol, followed by 400 μL of polyethylene glycol 400 (PEG 400), 50 μL of Tween-80, and finally 450 μL of double-distilled water (ddH2O). The solution was then sonicated for 5 minutes using an ultrasonic cell disruptor until clear, resulting in a final 1 mL solution with a Dio concentration of 30 mg / mL. The solvent control group solution was prepared identically to the control group solution, except that Dio was not added. All solutions were stored at 4°C and used within 24 hours.

[0039] Starting from the first day post-surgery, mice in the TAC+Dio group were administered Dio via gavage daily at a dose of 75 mg / kg / day. Mice in the Sham and TAC+Vehicle groups received an equal volume of the solution. The entire administration period lasted 4 weeks, and the experimental procedure is illustrated in the diagram below. Figure 1 As shown.

[0040] 3. Cardiac function testing Four weeks after drug administration, all mice underwent echocardiography using a small animal ultrasound imaging system (Vevo 2100, VisualSonics). Mice were lightly anesthetized, and their chest and abdomen were shaved. Two-dimensional images of the left ventricle's long and short axes, as well as M-mode ultrasound images, were acquired using a high-frequency probe. The accompanying analysis software was used to analyze images from at least three consecutive cardiac cycles, automatically calculating and recording the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) to assess cardiac contractile function. Results are as follows:Figure 2 As shown in A and 2B.

[0041] 4. Histopathological analysis of cardiac tissue After echocardiography, mice were euthanized and their hearts were quickly removed, rinsed with pre-cooled PBS, blotted dry, and weighed. The heart weight to tibia length ratio (HW / TL) was calculated. The heart tissue was fixed in 4% paraformaldehyde, embedded in paraffin, and then cut into 4-5 μm thick sections.

[0042] Hematoxylin-eosin (HE) staining: used to observe changes in the overall morphology and structure of the heart, such as... Figure 2 As shown in C.

[0043] Wheat germ agglutinin (WGA) staining: used to label cardiomyocyte membranes. The cross-sectional area of ​​at least 100 cardiomyocytes was randomly measured using ImageJ software to assess the degree of cardiomyocyte hypertrophy. Results are as follows: Figure 2 As shown in D and 2E.

[0044] 5. Detection of molecular markers related to myocardial hypertrophy The expression levels of hypertrophy-related genes and proteins in myocardial tissue were detected by real-time quantitative PCR (qRT-PCR) and Western blotting.

[0045] At the gene level: the mRNA expression levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC) were detected, and the results are as follows: Figure 2 As shown in F.

[0046] Protein levels: The protein expression levels of ANP and BNP were detected, and the results are as follows. Figure 2 As shown in G and 2H.

[0047] 6. Results Analysis like Figure 2 As shown, compared with the Sham group, mice in the TAC+Vehicle group showed significant decline in cardiac function, manifested by a marked decrease in LVEF and LVFS values. Figure 2 B); HE staining of the heart showed significant thickening of the ventricular wall (B); Figure 2 C); WGA staining showed a significant increase in the cross-sectional area of ​​cardiomyocytes (C); Figure 2 D, 2E); Simultaneously, the mRNA and protein expression levels of ANP, BNP, and β-MHC in myocardial tissue were significantly upregulated (D, 2E). Figure 2 (F, 2G, 2H). These results all indicate that TAC surgery successfully induced a mouse model of pathological myocardial hypertrophy.

[0048] Compared with the TAC+Vehicle group, the cardiac function parameters (LVEF and LVFS) of mice in the TAC+Dio group were significantly improved. Figure 2 B); cardiac structural remodeling and cardiomyocyte hypertrophy were significantly alleviated (B); Figure 2 C, 2D, 2E); the expression levels of myocardial hypertrophy markers were also significantly reduced ( Figure 2 (F, 2G, 2H). This embodiment demonstrates that diosgenin can effectively alleviate myocardial hypertrophy caused by stress load.

[0049] Comparative Example 1: Effects of diosgenin on cardiac function in sham-operated mice To rule out the potential toxicity or effects of diosgenin itself on normal heart function, we used a sham-operated mouse group treated with 75 mg / kg / day of Dio for 4 weeks (Sham+Dio group). Echocardiography and cardiac histological analysis showed no significant differences in LVEF, LVFS, cardiac structure, cardiomyocyte area, and hypertrophy marker expression between the Sham+Dio group and the Sham+Vehicle group. This indicates that at this dosage, diosgenin has no significant effect on normal cardiac function, and its effects are pathologically specific.

[0050] Example 2: Diosgenin alleviates heart failure caused by stress. 1. Animal models and drug administration To further investigate the long-term therapeutic effect of Dio on heart failure, we established a chronic heart failure model. The experimental animals, TAC surgical modeling method, grouping, and drug preparation were all the same as in Example 1, the only difference being that the drug administration period was extended to 7 weeks to ensure that the model mice progressed from myocardial hypertrophy to heart failure. A schematic diagram of the experimental procedure is shown below. Figure 3 As shown.

[0051] 2. Detection Indicators and Methods Seven weeks after administration, the small animals underwent echocardiography, and were subsequently euthanized and heart samples were collected.

[0052] Cardiac function testing: The method is the same as in Example 1, and the results are as follows. Figure 4 As shown in A and 4B.

[0053] Histopathological analysis of cardiac tissue: except for HE staining ( Figure 4 C) and WGA staining (to measure cardiomyocyte area), Figure 4 In addition to D, 4E), Masson's trichrome staining was performed to assess the degree of collagen deposition and fibrosis in the myocardial tissue, and the fibrosis area was quantitatively analyzed. The results are as follows: Figure 4 As shown in F.

[0054] Detection of heart failure-related molecular markers: The mRNA and protein expression levels of ANP and BNP were detected by qRT-PCR and Western Blot. The results are as follows: Figure 4 As shown in G, 4H.

[0055] 3. Results Analysis like Figure 4 As shown, after 7 weeks of stress, mice in the TAC+Vehicle group exhibited more severe heart failure, with a sharp decline in LVEF and LVFS. Figure 4 B); The heart volume is significantly enlarged, and the ventricular walls are thinned, presenting a typical phenotype of heart failure with cardiac dilation. Figure 4 A, 4C); cardiomyocyte hypertrophy ( Figure 4 D, 4E) and cardiac interstitial fibrosis ( Figure 4 F) were all extremely significant; molecular markers of heart failure were also consistently highly expressed (F) Figure 4 G, 4H, 4I).

[0056] The TAC+Dio group mice showed significant protection in all indicators: cardiac function was maintained at a high level. Figure 4 B), cardiac dilation and thinning of the ventricular wall are inhibited ( Figure 4 A, 4C), significantly reduced area of ​​cardiomyocyte hypertrophy and fibrosis ( Figure 5 D, 4E, 4F), downregulation of heart failure marker expression ( Figure 5 (G, 4H). This embodiment demonstrates that diosgenin can not only alleviate early myocardial hypertrophy, but also effectively delay or even prevent the progression of concentric failure.

[0057] Example 3: Identification of the target of diosgenin 1. Pull-down binding mass spectrometry analysis of small molecule biotin To identify the target of diosgenin, we first employed a small-molecule biotin pull-down technique. For example... Figure 6 As shown in Schematic A, we synthesized a biotin-labeled diosgenin derivative (Bio-Dio). Bio-Dio or biotin alone (as a negative control) was incubated with streptavidin magnetic beads to prepare affinity probes. These probes were then used to "fish" for interacting proteins from mouse heart tissue protein lysates. After thorough washing, the protein complexes bound to the probes were eluted and subjected to trypsin digestion.

[0058] The enzymatically digested peptide samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By comparing the mass spectrometry data of the Bio-Dio group and the biotin control group, proteins specifically binding to Bio-Dio were screened.Figure 6 As shown in B, among the candidate proteins with higher scores, heat shock protein 90 (HSP90) had the highest binding score, suggesting that it may be a direct target of diosgenin.

[0059] 2. Pull-down binding and surface plasmon resonance (SPR) verify direct interactions To further verify the binding of diosgenin to HSP90, we used a small-molecule biotin pull-down assay and detected the eluted protein using an HSP90 antibody. Figure 7 As shown in Figure A, diosgenin binds to HSP90 in cardiomyocytes and tissues. To determine the direct binding of diosgenin to HSP90, we performed surface plasmon resonance (SPR) experiments. Recombinant human HSP90 protein was immobilized on a CM5 sensor chip, and diosgenin (Dio) solutions of different concentrations were used as the mobile phase flowing through the chip surface. The results are shown in Figure A. Figure 8 As shown in Figure B, the SPR sensing plot shows that diosgenin can bind to the HSP90 protein in a dose-dependent manner, and its equilibrium dissociation constant (KD) was calculated to be 0.78 μM, which confirms that there is a high-affinity direct interaction between the two.

[0060] Example 4: Validation of the function dependence of diosgenin in HSP90-degraded mice 1. Construction and experimental design of HSP90 degradation mouse model To definitively demonstrate that the cardioprotective effect of diosgenin is indeed achieved through targeting HSP90, we utilized protein degradation-targeting chimera (PROTAC) technology to specifically degrade the HSP90 protein in mouse hearts in vivo. We administered HSP90-PROTAC adeno-associated virus (AAV9) carrying a heart-specific promoter via tail vein injection, while control mice were injected with an empty vector virus (AAV9-Control).

[0061] Three weeks after viral injection, it was confirmed that HSP90 protein had been effectively knocked down in the heart. Subsequently, these HSP90-degraded mice (hereinafter referred to as cHSP90KD ​​mice) and control mice underwent transarterial chemoradiolysis (TAC). Post-surgery, they were randomly divided into four groups: Control group + TAC + Vehicle (Control+TAC+Veh) Control group + TAC + Dio HSP90 degradation group + TAC + Vehicle (cHSP90KD+TAC+Veh) HSP90 degradation group + TAC + Dio (cHSP90KD+TAC+Dio) The dosing regimen (75 mg / kg / day, by gavage) and duration (4 weeks) were the same as in Example 1. A schematic diagram of the experimental procedure is shown below. Figure 8 As shown.

[0062] 2. Results Analysis Four weeks later, cardiac function and cardiac histology were performed on mice in each group. The results are as follows: Figure 8 As shown: In control mice, we replicated the results of Example 1: Dio administration (Control + TAC + Dio) significantly improved TAC-induced cardiac function decline ( Figure 8 D) and cardiomyocyte hypertrophy ( Figure 8 A, 8C, 8E).

[0063] However, in cHSP90KD ​​mice, the protective effect of Dio was almost completely lost. The cardiac function of mice in the cHSP90KD+TAC+Dio group ( Figure 8 B, 8D), heart morphology ( ​ A) and cardiomyocyte area ( ​ There were no significant differences between the C and 8E groups and the cHSP90KD+TAC+Veh group.

[0064] This key experiment demonstrates that diosgenin can no longer exert its anti-cardiomyopathy effect when the HSP90 protein in the heart is effectively degraded. This strongly proves that HSP90 is an indispensable key target for diosgenin to exert its cardioprotective function.

[0065] Comparative Example 2: Comparative Effects of the HSP90 Inhibitor Gerdomidine To compare the mechanism of action of diosgenin with that of diosgenin, we added a control group. Based on the wild-type mouse TAC model, in addition to the solvent and Dio groups, a group was given the classic HSP90 inhibitor geldanamycin (GA, 1 mg / kg / day, intraperitoneal injection). The results showed that while GA could also slightly alleviate myocardial hypertrophy to some extent, its effect was far weaker than Dio, and it caused significant liver toxicity (manifested as significant weight loss and elevated serum transaminase levels in mice), while no significant toxic side effects were observed in the Dio group. This comparison suggests that diosgenin, as a natural HSP90 "stabilizer," may have a different mechanism of action and safety profile than traditional HSP90 "inhibitors," demonstrating its unique therapeutic advantages.

[0066] In summary, this invention demonstrates through a series of in vitro and in vivo experiments that the natural small molecule compound diosgenin can effectively alleviate stress-induced myocardial hypertrophy and heart failure by directly targeting and binding to HSP90 and regulating downstream signaling pathways. This provides a solid experimental basis and a novel mechanism of action for its development into a new anti-heart failure drug.

[0067] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. Use of a diosgenin in the preparation of a medicament for the treatment of heart failure.

2. The use according to claim 1, characterized in that, The heart failure is heart failure caused by or related to stress load.

3. The use according to claim 2, characterized in that, The heart failure caused by the pressure load is due to the progression of cardiac hypertrophy; preferably, the diosgenin is used to alleviate or reverse myocardial hypertrophy.

4. The use according to any one of claims 1-3, characterized in that, The diosgenin works by targeting HSP90.

5. The use according to claim 4, characterized in that, The diosgenin binds directly to HSP90 and stabilizes the HSP90 protein.

6. The use according to claim 4 or 5, characterized in that, The diosgenin exerts its anti-heart failure effect by activating the HSP90 / LKB1 / AMPK signaling axis, maintaining mitochondrial function in cardiomyocytes, and / or enhancing fatty acid metabolism.

7. Use of a pharmaceutical composition in the preparation of a medicament for treating heart failure, said pharmaceutical composition comprising a therapeutically effective amount of diosgenin and a pharmaceutically acceptable carrier.

8. The use according to claim 7, characterized in that, The dosage of the pharmaceutical composition is 1 mg to 200 mg of diosgenin per kilogram of body weight per day; preferably, the dosage is 50 mg to 100 mg of diosgenin per kilogram of body weight per day; more preferably, the dosage is 75 mg of diosgenin per kilogram of body weight per day.

9. The use according to claim 7 or 8, characterized in that, The dosage form of the pharmaceutical composition is an oral dosage form; preferably, the oral dosage form is a tablet, capsule, granule or oral liquid.

10. A pharmaceutical composition for treating heart failure, characterized in that, Include: (i) A therapeutically effective amount of diosgenin is used as the active ingredient; (ii) pharmaceutically acceptable carriers; and, (iii) Optionally, excipients for enhancing solubility, said excipients including one or more of ethanol, polyethylene glycol and Tween-80.

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