Application of compound Hispidol or pharmaceutically acceptable salt thereof in preparation of lipophagy activator

Abstract

The invention discloses an application of a compound Hispidol or a pharmaceutically acceptable salt thereof in preparation of a lipophagy activator. The invention discovers and verifies for the first time that Hispidol can target lysosome, promote liver cell lipophagy and accelerate removal of lipid droplets in liver cells so as to relieve fatty degeneration. In a mouse MASH model, the Hispidol can also significantly promote lipophagy and relieve MASH. The invention relates to a novel application of a lysosome targeting mechanism of Hispidol in enhancing lipophagy activity of liver cells so as to remove lipid droplets and improve the pathological process of liver lipid accumulation and metabolic dysfunction related steatohepatitis (MASH).

Description

Technical Field

[0001] This invention relates to the use of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of lipophagus activators. It belongs to the field of biomedical technology. Background Technology

[0002] Lipophagy is the selective degradation of lipid droplets by cells through autophagy, playing a central role in maintaining cellular energy homeostasis. As a crucial bridge connecting autophagy and lipid metabolism, lipophage is activated under energy stress conditions such as starvation, providing energy to cells by breaking down lipid droplets. Furthermore, lipophage effectively removes excess or damaged lipid droplets, preventing abnormal accumulation of lipids in non-adipose tissues such as the liver and muscles, thereby avoiding the development of lipotoxicity, insulin resistance, and metabolic dysfunction-associated steatohepatitis (MASH). Studies have shown that lipophage dysfunction is also closely related to the progression of various metabolic diseases such as obesity, diabetes, and atherosclerosis. Therefore, lipophage is not only an important intracellular "scavenger" and "energy converter," but its functional stability is also crucial for metabolic health, making it a highly promising new target in metabolic disease treatment research.

[0003] Lipophagy, an autophagic process that selectively degrades lipid droplets, is a core mechanism for maintaining hepatic lipid homeostasis. Its dysfunction is a key driver in the development of metabolic dysfunction-associated steatohepatitis (MASH). Significantly impaired lipophage flux in MASH leads to a massive accumulation of triglycerides in hepatocytes, triggering lipotoxicity and exacerbating hepatic inflammation. Simultaneously, lipophage deficiency weakens the inhibitory effect on hepatic stellate cell activation, promoting liver fibrosis. Currently, mainstream lifestyle interventions have limited effectiveness in treating advanced MASH patients, and there are no approved drugs specifically targeting lipophage for MASH treatment. Therefore, the development of novel targeted therapeutic strategies is urgently needed.

[0004] Hispidol is a naturally derived orange ketone compound. Previous studies have suggested that it has broad-spectrum activities such as antioxidant, antibacterial and anti-inflammatory effects, but its effect on lipophagus remains unknown. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide the use of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of lipophagus activators.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: 1. The application of compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of lipophage activators, wherein the Chinese name of compound Hispidol is 6-hydroxy-2-[(4-hydroxyphenyl)methylene]-1-benzofuran-3-one, and its molecular formula is C2. 15 H 10 O4, with the structural formula as shown in formula (Ⅰ): .

[0007] As one of the preferred technical solutions, the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt, wherein the organic acid is selected from at least one of acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, and oxalic acid; and the inorganic acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, and nitric acid.

[0008] As one of the preferred technical solutions, the compound Hispidol or a pharmaceutically acceptable salt thereof promotes lipophagy by facilitating the fusion of lipid droplets with lysosomes and / or enhancing the degradation function of the autophagy-lysosomal pathway.

[0009] As one of the preferred technical solutions, the compound Hispidol or a pharmaceutically acceptable salt thereof promotes lipophagy by promoting the degradation of the lipid droplet surface protein PLIN-2.

[0010] 2. The use of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of drugs for the prevention or treatment of hepatic lipid accumulation and related diseases.

[0011] As one of the preferred technical solutions, the liver lipid accumulation and related diseases are metabolic dysfunction-associated steatohepatitis (MASH).

[0012] As a further preferred technical solution, the metabolic dysfunction-related steatohepatitis is caused by lipid metabolism disorder.

[0013] As a further preferred technical solution, the compound Hispidol or a pharmaceutically acceptable salt thereof treats metabolic dysfunction-related steatohepatitis by activating lipophage in hepatocytes.

[0014] As one of the preferred technical solutions, the compound Hispidol or its pharmaceutically acceptable salt is independent of its inhibitory activity against monoamine oxidases MAO-A / B.

[0015] 3. A pharmaceutical composition comprising the compound Hispidol or a pharmaceutically acceptable salt thereof.

[0016] 4. A formulation in which the active ingredient is the compound Hispidol or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned.

[0017] As one of the preferred technical solutions, the preparation is an oral preparation.

[0018] Beneficial effects of the present invention: This invention discloses the application of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of lipophagus activators. This invention is the first to discover and demonstrate that Hispidol can target lysosomes, promote hepatocyte lipophagus, and accelerate the clearance of lipid droplets within hepatocytes to alleviate steatosis. In a mouse MASH model, Hispidol also significantly promotes lipophagus and alleviates MASH. This invention relates to a novel use of Hispidol's lysosomal targeting mechanism to enhance hepatocyte lipophagus activity, thereby clearing lipid droplets, improving the pathological progression of hepatic lipid accumulation and metabolic dysfunction-associated steatohepatitis (MASH). Attached Figure Description

[0019] Figure 1. Hispidol reduces intracellular lipid accumulation in hepatocytes; A. Hispidol reduces OA-induced intracellular lipid accumulation in AML12 hepatocytes; B. Statistical results of Oil Red O staining in A; C. The half-maximal effective dose of Hispidol for reducing intracellular TG content in AML12 hepatocytes was 2.330 μM; D. Hispidol reduces intracellular TG levels in AML12 hepatocytes; E. Lipi-Green staining visualization analysis of intracellular lipid accumulation in hepatocytes; Statistical results of Lipi-Green staining in F. E.

[0020] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the OA group and the Hispidol group (***: p < 0.001).

[0021] Figure 2. Hispidol is localized in lysosomes; A. Chemical synthesis steps of Biotin-Hispidol; B. Mass spectrometry analysis of Biotin-Hispidol in A; C. Liquid chromatography analysis of the purity of Biotin-Hispidol in A; D. Observe the subcellular localization of Biotin-Hispidol in A in AML12 and HeLa cells; E. Quantitative analysis of colocalization of Biotin-Hispidol with lysosomes in D.

[0022] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the Biotin group and the Biotin-Hispidol group (***: p < 0.001).

[0023] Figure 3. Hispidol promotes lipoautophagy; A. Hispidol promotes colocalization of lipid droplets and lysosomes; B. Quantitative analysis of colocalization of lipid droplets and lysosomes in A; C. Baf A1 or Lalistat 1 block the lipid-lowering activity of Hispidol; D. Hispidol enhances OA-induced degradation of the key lipid droplet protein PLIN-2.

[0024] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the DMSO group and the Hispidol group (***: p < 0.001).

[0025] Figure 4. Low-dose Hispidol can alleviate HFD-induced MASH in mice; A. Flowchart of HFD-induced MASH model in mice; B. Actual image of a MASH mouse liver; C. H&E staining results of MASH mouse liver; D. Hispidol reduces TG levels in mouse liver tissue; Results of Oil Red O staining in the liver of E. MASH mice; Quantitative analysis of Oil Red O staining results in the livers of F. MASH mice; G. Hispidol enhances the degradation of PLIN-2, a key lipid droplet protein, in the liver tissue of HFD mice.

[0026] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the MCD group and the drug-treated group (**: p < 0.01; ***: p < 0.001).

[0027] Figure 5. Hispidol does not affect lipid absorption; A. Flow cytometry analysis of the effect of Hispidol on FITC-OA uptake in AML12 hepatocytes; B. Statistical results of Hispidol's effect on FITC-OA uptake in AML12 hepatocytes; C. Hispidol reduces lipid accumulation in AML12 hepatocytes in a time-dependent manner.

[0028] All values ​​are presented as mean ± standard deviation (n = 3). ns: There was no statistically significant difference between the Vehicle group and the Hispidol group (ns: no significant).

[0029] Figure 6. Hispidol reduces lipid accumulation without relying on its inhibitory activity against MAO-A / B; A. MAO-A was knocked down in AML12 hepatocytes using shRNA technology; B. MAO-B was knocked down in AML12 hepatocytes using shRNA technology; C. Statistical analysis of the results of Hispidol reducing lipid accumulation in AML12 shMAO-A / B hepatocytes.

[0030] All values ​​are presented as mean ± standard deviation (n = 3). ns: Statistically significant difference between the OA group and the treated group (ns: no significant).

[0031] Figure 7. The lipid-lowering effect of the quinone compound Hispidol is superior to that of flavonoids; A. Chemical structural formula of Hispidol; B. Chemical structural formula of Baicalein; Chemical structural formula of C. Kaempferol; D. Chemical structural formula of Luteolin; E. Orange ketones and flavonoids reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes.

[0032] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the OA group and the drug group (*: p < 0.05; ***: p < 0.001).

[0033] Figure 8. The lipid-lowering effect of the chalcone compound isoliquiritigenin is independent of lipophagus; A. Isoliquiritigenin reduces OA-induced intracellular lipid accumulation in AML12 hepatocytes; B. Isoliquiritigenin did not promote colocalization of lipid droplets and lysosomes; C. Quantitative analysis of colocalization of lipid droplets and lysosomes in B; D. Isoliquiritigenin did not enhance OA-induced degradation of the key lipid droplet protein PLIN-2.

[0034] All values ​​are presented as mean ± standard deviation (n = 3). *: There was a statistically significant difference between the DMSO group and the Hispidol group (*: p < 0.05, ns: no significant).

[0035] Figure 9. The lipid-lowering activity of Hispidol is related to the substitution sites and number of hydroxyl groups in its molecular structure; A. Hispidol structural formula and its ability to reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes; B. SKI V structural formula and its ability to reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes; C. Sulfuretin structural formula and its ability to reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes; D. The structural formula of homologue 596 and its reduction of OA-induced intracellular lipid accumulation in AML12 hepatocytes; E. Structural formula of homologue 591-1 and its ability to reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes; F. The structure of the orange ketone core 051 and its ability to reduce OA-induced intracellular lipid accumulation in AML12 hepatocytes. Detailed Implementation

[0036] The present invention will be further described below with reference to the accompanying drawings and embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its content.

[0037] Example 1: Hispidol Reduces Intracellular Lipid Accumulation in Hepatocytes. After AML12 cells (ATCC: Cat#CRL-2254) were seeded to 80% of the bottom of a 6-well plate, a cellular lipid accumulation model was established (Phytomedicine. 2021 Jan;81:153412). Oleic acid (OA: 400 μM; MCE: Cat#HY-N1446) was added to the AML12 cell culture medium (Shanghai Yuanpei: Cat#L110KJ). Oil Red O staining revealed that OA stimulation significantly increased intracellular lipid accumulation, while Hispidol (MCE: Cat#HY-102040) reduced intracellular lipid levels (Figure 1, A, B). The antioxidant NAC (MCE: Cat#HY-B0215) did not clear OA-induced intracellular lipid accumulation (Figure 1, A, B). The IC50 of Hispidol inhibiting intracellular lipid accumulation was 2.330. μM (C and D in Figure 1), and Lipi-Green staining further confirmed that Hispidol can reduce intracellular lipid levels (E and F in Figure 1).

[0038] The results show that Hispidol can significantly reduce intracellular lipid accumulation in hepatocytes.

[0039] Example 2: Hispidol Localization in Lysosomes To elucidate the molecular mechanism by which Hispidol regulates intracellular lipid metabolism, this invention designed and synthesized a biotin-labeled Hispidol derivative (hereinafter referred to as "Biotin-Hispidol"). Specifically, by covalently linking a biotin group (Figure 2A) to the 6th hydroxyl site of the Hispidol molecule, a compound with a well-defined structure was obtained. The specific synthetic steps are as follows: 1) Dissolve S1, S4, Cs2CO3 and NaI (A in Figure 2) in DMF, heat and stir at 65°C overnight. After the reaction is complete, add water and extract with EA (ethyl acetate). Combine the organic phases and back-extract successively with 1M NaOH aqueous solution and saturated NH4Cl. Concentrate the organic phase and purify it by column chromatography. 2) Dissolve S3 in methanol, add 50% KOH solution, and then add M2; heat and stir at 60℃ for 2-3 hours. After the reaction is complete, evaporate the solvent, add water, and adjust the pH to acidic with 6M HCl. A large amount of solid precipitates out. Filter the solid and purify the filter cake by column chromatography to obtain a yellow solid. 3) Dissolve M3 in DCM (dichloromethane), add trifluoroacetic acid, stir at room temperature for 1-2 h, evaporate to dryness after the reaction is complete, then dissolve in DCM, add DIPEA (N,N-diisopropylethylamine) until no more fumes are emitted; 4) Dissolve S5 in DCM, add HATU and DIPEA, stir at room temperature for 15-30 min, add the solution from the previous step, stir at room temperature overnight, and after the reaction is complete, evaporate the solvent, then add water, and a large amount of solid precipitates out. Filter, and purify the filter cake by column chromatography to obtain a yellow solid. Further purify by reversed-phase HPLC to finally obtain a bright yellow solid.

[0040] Mass spectrometry analysis (Figure 2, B) and liquid chromatography detection (Figure 2, C) showed that the synthesized Biotin-Hispidol possessed the expected chemical structure and its purity met the requirements for chemical biology experiments. Subcellular localization studies in AML12 hepatocytes and HeLa cells revealed significant co-localization between Biotin-Hispidol and lysosomal markers (Figure 2, D and E). This result indicates that Hispidol is primarily enriched in the lysosomal region within cells. These results suggest that Hispidol is mainly localized in lysosomes intracellularly, regulating intracellular lipid metabolism and thus reducing lipid accumulation by acting on lysosomal pathways.

[0041] Example 3: Hispidol Promotes Lipautophagy. To elucidate the mechanism by which Hispidol regulates intracellular lipid metabolism via the lysosomal pathway, this invention observed in an oleic acid (OA)-induced AML12 hepatocyte steatosis model that Hispidol treatment significantly enhanced the co-localization of lipid droplets and lysosomes (Figure 3A, B), suggesting that it may promote the transport or recruitment of lipid substances to the lysosomal region. Baf A1 (1 μM; MCE: Cat#HY-100558) is a specific, reversible V-ATPase inhibitor that blocks the fusion of autophagosomes and lysosomes, and LAListat1 (1 μM; MCE: Cat#HY-116815) is a potent, selective, and competitive lysosomal acid lipase inhibitor. The addition of these two inhibitors to AML12 cells significantly blocked the effect of Hispidol in reducing intracellular lipid content (Figure 3C). This result indicates that the lipid-lowering activity of Hispidol depends on the intact autophagy-lysosomal degradation function. Further validation in an OA-induced AML12 cell model revealed that Hispidol treatment promoted the degradation of the key lipid droplet protein perilipin-2 (PLIN-2) (Figure 3D). These cellular experimental results indicate that Hispidol can reduce lipid accumulation in hepatocytes by activating the autophagy-lysosomal pathway and enhancing intracellular lipophagy.

[0042] Example 4: Low-dose Hispidol alleviates HFD-induced MASH in mice. In this example, male C57BL / 6 mice (Cyagen (Suzhou) Biotechnology Co., Ltd.; Certificate No.: No. 320981250100618075) were used to test whether low-dose Hispidol could alleviate the pathological process of HFD-induced MASH in mice (Europace. 2023 Dec 28;26(1):euae004). Hispidol was dissolved in corn oil to prepare a suspension of 0.1 mg / ml. The corresponding dose of Hispidol or the solvent was administered by gavage to mice according to their body weight (10 ml / kg) every 3 days for a total of 120 days (Figure 4A). Half an hour after the last gavage with Hispidol, the mice were treated and their liver and serum were collected for testing.

[0043] The protective effect of Hispidol was investigated. Results showed that Hispidol significantly alleviated liver damage (Figure 4, B and C); Oil Red O staining and TG detection of liver homogenate indicated that Hispidol could reduce lipid accumulation in mouse liver (Figure 4, DF); simultaneously, Hispidol promoted the degradation of the key lipid droplet protein PLIN-2 in the liver tissue of HFD mice (Figure 4, G).

[0044] The above results suggest that low-dose Hispidol can also reduce HFD-induced lipid accumulation in the liver of MASH mice by promoting lipophagy.

[0045] Example 5: Hispidol does not affect lipid uptake. To investigate the effect of hispidol on lipid uptake and metabolism, the effect of hispidol on lipid uptake was examined in AML12 cells. The results showed that hispidol did not change the lipid uptake of AML12 cells (Figure 5A, B), and hispidol required a relatively long time to clear intracellular lipid accumulation (Figure 5C). These results indicate that hispidol did not affect lipid uptake by hepatocytes, but promoted the clearance of intracellular lipids.

[0046] Example 6: Hispidol's reduction of lipid accumulation is independent of its inhibitory activity against MAO-A / B. Previous studies have found that Hispidol can act as a monoamine oxidase (MAO-A / B) inhibitor, exerting antioxidant and lifespan-extending effects. To investigate whether Hispidol's lipid accumulation-inhibiting activity depends on its inhibitory activity against MAO-A / B, MAO-A / B expression was knocked down in AML12 cells using shRNA technology (Figure 6, A and B). The results, as shown in Figure 6, C, indicate that knocking down MAO-A / B did not alter OA-induced lipid accumulation in AML12 cells, while 10 μM Hispidol significantly reduced lipid accumulation in AML12 shMAO-A / B cells.

[0047] Example 7: Hispidol, an orange ketone compound, has a better lipid-lowering effect than flavonoids. To further compare the lipid-lowering effects of Hispidol and flavonoids, a cell lipid accumulation model was established after AML12 cells covered 80% of the bottom of a 6-well plate: OA was added to the AML12 cell culture medium.

[0048] Based on this model, the effects of the orange ketone compound Hispidol and the flavonoid compounds baicalein (MCE: Cat# HY-N0196), kaempferol (MCE: Cat# HY-14590), and luteolin (MCE: Cat# HY-N0162) on reducing intracellular lipid accumulation were examined (AD in Figure 7). The results showed that Hispidol had a significantly better lipid-lowering effect than baicalein, kaempferol, and luteolin (E in Figure 7).

[0049] Example 8: The lipid-lowering effect of the chalcone compound isoliquiritigenin is independent of lipophage. To clarify the specificity of Hispidol's lipid-lowering function through lipophage activation, the applicant screened chalcones with existing patent protection as controls (authorization number: TWI634886B). The results showed that isoliquiritigenin (MCE:Cat#HY-N0102) could reduce OA-induced intracellular lipid accumulation in hepatocytes (Figure 8A). However, no changes in the co-localization of lipid droplets and lysosomes were observed after Isoliquiritigenin treatment (Figure 8B, C). Further, in an OA-induced AML12 cell model, Isoliquiritigenin treatment did not promote the degradation of the key protein perilipin-2 (PLIN-2) on the surface of lipid droplets (Figure 8D). The above cell experimental results indicate that the reduction of intracellular lipid accumulation by chalcone is independent of lipophage, which also reflects the specificity of Hispidol in reducing intracellular lipid accumulation by promoting lipophage.

[0050] Example 9: The lipid-lowering activity of Hispidol is related to the substitution sites and number of hydroxyl groups in its molecular structure. To clarify the structure-activity relationship of Hispidol in reducing lipid accumulation, the present invention synthesized or obtained Hispidol structural analogs with different numbers and positions of hydroxyl substitution. Among them, SKI V (Cat#HY-12895, B in Figure 9) and sulfuretin (Cat#HY-N1193, C in Figure 9) were purchased from MCE. 1) The synthesis scheme of 051 is as follows: Benzofurone and benzaldehyde are dissolved in methanol, and 50% KOH solution is added; the mixture is heated and stirred at 60 °C for 1 h. After the reaction is complete, the solvent is evaporated, water is added, and the pH is adjusted to acidic with 6M HCl; the mixture is extracted with EA, the organic phases are combined and prepared into sand, and purified by silica gel column chromatography to obtain a yellow solid. The solid is further purified by reversed-phase HPLC to finally obtain a white to pale yellow solid (F in Figure 9). 2) The synthesis scheme of 596 is as follows: Benzofuranone and p-hydroxybenzaldehyde are dissolved in methanol, and 50% KOH solution is added; the mixture is heated and stirred at 60 °C for 1 h; after the reaction is complete, the solvent is evaporated, water is added, and the pH is adjusted to acidic with 6M HCl; the mixture is extracted with EA, the organic phases are combined and prepared into a slurry, and purified by silica gel column chromatography to obtain a bright yellow solid. The slurry is further purified by reversed-phase HPLC to finally obtain a yellow solid (D in Figure 9). 3) The synthesis scheme of 591-1 is as follows: Dissolve 3-hydroxybenzofuranone and benzaldehyde in water, add KOH; stir at room temperature for 3-4 h, and after the reaction is complete, adjust the pH to acidic with 6M HCl; filter, dissolve the filter cake to make sand, purify by silica gel column chromatography to obtain a bright yellow solid, further purify by reversed phase HPLC, then slurry, precipitate the solid, filter, and finally obtain a yellow solid (E in Figure 9).

[0051] The lipid-lowering activity of the above Hispidol homologues was tested after OA induction. The results showed that the lipid-lowering effect of Hispidol was significantly dependent on the number and position of hydroxyl groups in its core structure (AE in Figure 9), while the non-hydroxyl-substituted orange ketone core structure did not show a significant improvement effect on OA-induced intracellular lipid accumulation. Figure 9 (F). The above results indicate that the lipid-lowering activity of Hispidol is closely related to the substitution position and number of hydroxyl groups in its molecule.

[0052] This invention illustrates the application of Hispidol in the preparation of medicaments for the prevention and / or treatment of MASH through the above embodiments. However, this invention is not limited to the above embodiments, i.e., it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of this invention, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

Claims

1. The use of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of lipophage activators, characterized in that, The compound Hispidol has the Chinese name 6-hydroxy-2-[(4-hydroxyphenyl)methylene]-1-benzofuran-3-one and the molecular formula C2. 15 H 10 O4, with the structural formula as shown in formula (Ⅰ): 。 2. The application according to claim 1, characterized in that, The pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt, wherein the organic acid is selected from at least one of acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, and oxalic acid; and the inorganic acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, and nitric acid.

3. The application according to claim 1, characterized in that, The compound Hispidol or a pharmaceutically acceptable salt thereof promotes lipophagy by facilitating the fusion of lipid droplets with lysosomes and / or enhancing the degradation function of the autophagy-lysosomal pathway.

4. The application according to claim 1, characterized in that, The compound Hispidol or a pharmaceutically acceptable salt thereof promotes lipophagy by facilitating the degradation of the lipid droplet surface protein PLIN-2.

5. The use of the compound Hispidol or a pharmaceutically acceptable salt thereof in the preparation of drugs for the prevention or treatment of hepatic lipid accumulation and related diseases.

6. The application according to claim 5, characterized in that, The liver lipid accumulation and related diseases mentioned are metabolic dysfunction-related steatohepatitis.

7. The application according to claim 6, characterized in that, The metabolic dysfunction-related steatohepatitis mentioned above is caused by lipid metabolism disorders.

8. The application according to claim 6, characterized in that, The compound Hispidol or a pharmaceutically acceptable salt thereof treats metabolic dysfunction-related steatohepatitis by activating lipophage in hepatocytes.

9. A pharmaceutical composition comprising the compound Hispidol or a pharmaceutically acceptable salt thereof.

10. A formulation, characterized in that, Its active ingredient is the compound Hispidol or a pharmaceutically acceptable salt thereof, or it comprises the pharmaceutical composition of claim 9.

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