A drug targeting JOSD2 gene or protein for treating metabolic-related fatty liver disease

Abstract

The present invention discloses a drug for treating metabolic-related fatty liver disease using the JOSD2 gene or protein as a target, belonging to the field of biomedicine technology. The drug comprises a substance that upregulates JOSD2 gene expression or enhances JOSD2 protein function. The present invention, for the first time, confirms the novel function of the JOSD2 gene and its encoded protein in MAFLD through in vitro and in vivo experiments, confirming that JOSD2 is a protective factor in MAFLD, and that increasing JOSD2 expression or enhancing its activity can treat MAFLD. This serves as a drug target for the development of drugs to treat MAFLD. The present invention provides a novel target for the clinical treatment of MAFLD and offers new ideas and perspectives for the development of innovative drugs for MAFLD.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of JOSD2 gene or JOSD2 protein as a drug target in the preparation of a drug for treating metabolism-related fatty liver disease. Background Art

[0002] Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease worldwide. Currently, approximately 38% of adults worldwide suffer from MAFLD, and its prevalence is expected to increase further in the next decade. MAFLD refers to a disease induced by factors other than alcohol and other factors that clearly induce liver damage. Its typical pathological feature is the excessive accumulation of lipids, mainly cholesterol (TC) and triglycerides (TG), in hepatocytes. As the disease progresses, MAFLD will further develop into metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and liver cirrhosis.

[0003] Due to the extremely complex pathogenesis and pathological process of MAFLD, the current clinical treatment options for MAFLD are very limited. Symptoms are mainly improved by changing dietary habits, increasing physical exercise, and supplemented with symptomatic drugs. There is no effective and specific drug for the treatment of MAFLD.

[0004] Therefore, in-depth research on the pathogenesis of MAFLD and revealing the key functional proteins that play a vital role in it are expected to provide new targets for the clinical treatment of MAFLD, and also provide new ideas for the development of innovative anti-MAFLD drugs.

[0005] Josephin domain containing 2 (JOSD2) belongs to the Machado-Joseph Deubiquitinase (MJDs) family of deubiquitinases. In addition to JOSD2, the family also includes JOSD1, ATXN3 (Ataxin3), and ATXN3L (Ataxin 3-like). To date, there are few studies on the biological functions of JOSD2, mainly focusing on the fields of tumors and cardiovascular diseases. Studies have reported that JOSD2 can promote the abnormal growth of intrahepatic cholangiocarcinoma by regulating the key effector YAP / TAZ of the Hippo signaling pathway through deubiquitination (ActaPharmaceutica Sinica B, 2021, 11(12): 4008-4019.), and can also inhibit LKB1 activity by removing the K6 ubiquitin chain of LKB1 protein, thereby promoting the malignant proliferation of non-small cell lung cancer (Signal Transduction and Targeted Therapy volume, 2024, 9: 11). In addition, some studies have shown that JOSD2 can inhibit the ubiquitination degradation of SERCA2a protein by mediating its deubiquitination regulation, thereby improving calcium handling in cardiomyocytes and alleviating cardiac hypertrophy and dysfunction (Nature Cardiovascular Research volume, 2023, 2:764-777.).

[0006] This suggests that JOSD2 plays a key role in the progression of diseases such as cancer and cardiovascular disease, but its role in chronic liver diseases such as MAFLD and MASH has not yet been reported domestically or internationally. Therefore, clarifying the role of JOSD2 in MAFLD is expected to provide experimental evidence for the development of JOSD2 as a drug target for the treatment of MAFLD. Summary of the Invention

[0007] The purpose of the present invention is to explore the genes / proteins related to the occurrence and development of metabolic-related fatty liver disease, use them as targets for the prevention and treatment of metabolic-related fatty liver disease, and screen drugs for the treatment of metabolic-related fatty liver disease.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] The present invention provides the use of the JOSD2 gene or the protein encoded by it as a target in the preparation of a drug for treating metabolism-related fatty liver disease. The drug contains a substance that upregulates JOSD2 gene expression or enhances JOSD2 protein function.

[0010] The present study found that the JOSD2 gene or its encoded protein plays a key role in the progression of metabolic-related fatty liver disease. Specifically, the study found that the expression of JOSD2 protein in the liver tissue of the MAFLD model induced by a high-fat, high-cholesterol diet was significantly downregulated, and liver-specific knockout of JOSD2 accelerated the progression of MAFLD induced by a high-fat, high-cholesterol diet, mainly manifested by exacerbated lipid accumulation in the liver, increased body weight and liver weight, increased serum alanine transaminase (ALT), aspartate aminotransferase (AST), TC and low-density lipoprotein cholesterol (LDLC) levels, increased TC and TG levels in liver tissue, and promoted the occurrence of inflammation; in addition, the study also found that exogenous overexpression of JOSD2 can alleviate the hepatocyte lipid accumulation induced by palmitic acid / oleic acid (PAOA).

[0011] The above studies show that JOSD2 expression has a negative regulatory effect on the progression of MAFLD. Taking JOSD2 as a target and using drugs that increase JOSD2 expression or enhance its activity can be used to treat MAFLD.

[0012] Furthermore, the metabolism-related fatty liver disease is induced by a high-fat and high-cholesterol diet.

[0013] Furthermore, the manifestations of the metabolic-related fatty liver disease include liver enlargement and excessive accumulation of lipids in the liver.

[0014] Furthermore, the metabolic-related fatty liver disease includes one or more of metabolic-related fatty liver hepatitis, liver fibrosis, cirrhosis and other chronic liver diseases.

[0015] Furthermore, the coding sequence of the human JOSD2 gene is shown in SEQ ID NO. 1, and the amino acid sequence of the encoded protein is shown in SEQ ID NO. 2; the coding sequence of the mouse Josd2 gene is shown in SEQ ID NO. 3, and the amino acid sequence of the encoded protein is shown in SEQ ID NO. 4. The applicable subjects of the present invention are not limited to humans or mice.

[0016] The present invention develops a pharmaceutical preparation for upregulating protein expression or enhancing protein activity targeting the JOSD2 gene or JOSD2 protein. The pharmaceutical preparation achieves the purpose of treating metabolic-related fatty liver disease by increasing JOSD2 expression or enhancing its activity.

[0017] Furthermore, the substance that upregulates JOSD2 gene expression is an adenovirus recombinant vector (AAV-JOSD2) that overexpresses JOSD2. The substance that enhances JOSD2 protein function is a purified JOSD2 protein or active polypeptide. The present invention is not limited to this embodiment and is applicable to any biologically safe JOSD2 product that targets JOSD2.

[0018] Furthermore, substances that upregulate JOSD2 gene expression or enhance JOSD2 protein function can modulate JOSD2 expression or enhance its activity, including but not limited to compound preparations and Chinese herbal medicines. Chinese herbal medicines or other drugs that can upregulate JOSD2 expression or enhance its activity fall within the scope of protection of this invention.

[0019] Furthermore, the drug also includes a pharmaceutically acceptable carrier, which is any preparation or carrier medium that can deliver an effective dose of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or the subject.

[0020] Furthermore, the dosage form of the drug is any one of tablets, granules, solutions, emulsions, suspensions, and capsules. The drug is prepared according to a preparation method described in pharmaceutics.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] This study, for the first time, demonstrates the crucial role of the JOSD2 gene and its encoded protein in MAFLD through in vitro and in vivo experiments. Using a recognized high-fat, high-cholesterol diet-induced MAFLD model, the study found that JOSD2 was significantly downregulated in the liver tissue of the MAFLD model. Furthermore, liver-specific JOSD2 knockout promoted lipid accumulation in the liver, increased body and liver weight, increased serum ALT, AST, TC, and LDLC levels, and liver TC and TG levels, and promoted inflammatory responses in the liver, thereby exacerbating the high-fat, high-cholesterol diet-induced MAFLD disease progression. Exogenous overexpression of JOSD2 ameliorates MAFLD symptoms. These studies confirm that JOSD2 is a protective factor in MAFLD, and increasing JOSD2 expression or enhancing its activity can treat MAFLD. Therefore, using this as a drug target could be a promising target for the development of drugs to treat MAFLD.

[0023] The present invention provides a new target for the clinical treatment of MAFLD and offers new ideas and perspectives for the development of innovative drugs for MAFLD. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1JOSD2 was significantly downregulated in the liver tissues of mice with MAFLD model induced by a high-fat, high-cholesterol diet; (A) Anatomical diagram of mice in the normal control (NC) and high-fat, high-cholesterol (HFHC) diet groups; (B) Liver images of mice in the NC and HFHC groups; (C) Protein immunoblotting to detect the expression of JOSD2 protein in the liver tissues of mice in the NC and HFHC groups.

[0025] Figure 2 PAOA reduces JOSD2 protein expression in hepatocytes in a concentration-dependent and time-dependent manner; (A) Protein immunoblotting detected the effect of different concentrations of PAOA on JOSD2 protein expression in hepatocytes HL7702; (B) Protein immunoblotting detected the effect of different concentrations of PAOA on JOSD2 protein expression in primary mouse hepatocytes; (C) Protein immunoblotting detected the effect of PAOA on JOSD2 protein expression in hepatocytes HL7702 at different treatment times.

[0026] Figure 3 Liver-specific knockout of JOSD2 exacerbates the disease progression of a high-fat, high-cholesterol diet-induced MAFLD model. (A) Real-time quantitative PCR was used to detect Josd2 gene expression in different organs of wild type (WT) and liver-specific knockout (HKO) JOSD2 mice. (B) An electronic balance was used to regularly monitor the body weight of mice in each group. (C) Liver images and liver weights of mice in each group.

[0027] Figure 4 Liver-specific knockout of JOSD2 increased the levels of ALT, AST, TC, LDLC in mouse serum and TC and TG in liver tissue; (AD) A blood biochemical analyzer was used to detect the levels of ALT, AST, TC, and LDLC in the serum of mice in each group; (EF) A kit was used to detect the levels of TC and TG in the liver tissue of mice in each group.

[0028] Figure 5Liver-specific knockout of JOSD2 exacerbates lipid accumulation in liver tissue, promotes the synthesis and uptake of cholesterol and fatty acids, and inhibits fatty acid β-oxidation; (A) Hematoxylin and eosin (H&E), Oil red O (Oil red O), and Sirius red staining of liver tissue sections from mice in each group; (B) Real-time quantitative PCR was used to detect the expression of cholesterol synthesis and metabolism genes, as well as fatty acid synthesis, uptake, and β-oxidation genes in liver tissues of normal mice and mice with liver-specific knockout of JOSD2 fed a high-fat, high-cholesterol diet.

[0029] Figure 6 Liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue; wherein: (A) Protein immunoblotting was used to detect the activation of the inflammatory signaling pathway IKKβ / NF-κB in the liver tissue of each group of mice; (B) Real-time quantitative PCR technology was used to detect the expression of inflammatory-related genes in the liver tissue of normal mice and liver-specific knockout JOSD2 mice fed a high-fat and high-cholesterol diet.

[0030] Figure 7 Overexpression of JOSD2 can alleviate PAOA-induced lipid accumulation in hepatocytes; Oil red O staining was used to detect the triglyceride content in hepatocytes of the normal group and the JOSD2 overexpression group after PAOA treatment. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific examples. The following examples are only used to illustrate the present invention and are not intended to limit the scope of application of the present invention. Without departing from the spirit and essence of the present invention, modifications or replacements made to the inventive method, steps or conditions all fall within the scope of the present invention.

[0032] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

[0033] Mice: C57BL / 6 male mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd., ALB-cre mice were purchased from Shanghai South Model Organisms Science Co., Ltd., JOSD2 conditional knockout mice were provided by Beijing Biocytogen Biotech Co., Ltd., and liver-specific JOSD2 knockout mice were generated by crossing JOSD2 conditional knockout mice with ALB-cre mice. High-fat, high-cholesterol diets were purchased from Research Diet (USA) (Cat. No. D09100310). Mice were fed a normal diet and a high-fat, high-cholesterol diet starting at 8 weeks of age and continued for 18 weeks.

[0034] Cells: Hepatocytes HL7702 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences, and primary mouse liver cells were isolated and obtained by collagenase digestion.

[0035] Inducers: Palmitic acid (PA, Catalog No. P5585) and oleic acid (OA, Catalog No. O1008) were purchased from Sigma-Aldrich. Preparation: Weigh a certain amount of oleic acid and palmitic acid and dissolve them in 0.1 M sodium hydroxide solution (heated in a 75°C water bath) to prepare 0.1 M PA and OA stock solutions, respectively. The PA and OA stock solutions were then mixed at a volume ratio of 1:2 to prepare a 0.1 M PAOA stock solution.

[0036] Western blotting: JOSD2 antibody (catalog number: SAB2103354) was purchased from Sigma-Aldrich, GAPDH antibody (catalog number: db106) and β-Actin (catalog number: db7283) were purchased from Hangzhou Daige Biotechnology Co., Ltd., p-IKKβ (Tyr188) antibody (catalog number: 347345), IKKβ antibody (catalog number: R24676), and IKBα antibody (catalog number: R23322) were purchased from Chengdu Zhengneng Biotechnology Co., Ltd., p-P65 (S529) antibody (catalog number: ET1604-27), P65 antibody (catalog number: ER0815), and p-IKBα (S32) antibody (catalog number: ET1609-78) were purchased from Hangzhou Huaan Biotechnology Co., Ltd.

[0037] Fluorescence quantitative PCR primers are shown in Table 1:

[0038] Table 1

[0039]

[0040]

[0041] Serum ALT, AST, TC, and LDL-C levels were measured: ALT detection kits (ab282882), AST detection kits (ab263882), and LDL-C detection kits (ab65390) were purchased from abcam, and TC detection kits (A111-2-1) and TG detection kits (A110-2-1) were purchased from Nanjing Jiancheng Bioengineering Institute. Testing was performed according to the kit instructions.

[0042] H&E staining: H&E staining solution (C0107) was purchased from Beyotime Biotechnology Co., Ltd. The test method was carried out according to the kit instructions.

[0043] Oil Red O staining: The Oil Red O staining kit (C0157M) was purchased from Beyotime Biotechnology Co., Ltd. The test method was performed according to the kit instructions.

[0044] Sirius red staining: The modified Sirius red staining kit (G1472) was purchased from Solebao Biotechnology Co., Ltd. The test method was carried out according to the kit instructions.

[0045] Example 1: Downregulation of JOSD2 expression in liver tissue of MAFLD model mice

[0046] 1. 8-week-old C57BL / 6 male mice were selected and fed with normal diet or high-fat and high-cholesterol diet for 18 weeks. The livers of the mice were dissected and photographed.

[0047] like Figure 1 As shown in Figures A and B, compared with the normal feed group, a large amount of white fat was observed in the abdominal cavity of mice in the high-fat and high-cholesterol diet group, and the liver was enlarged, soft, yellowish in color, and greasy, indicating that the MAFLD model was successfully established.

[0048] 2. The expression of JOSD2 protein in the liver tissue of mice in the normal diet group and the high-fat and high-cholesterol diet group was examined by protein immunoblotting.

[0049] like Figure 1 As shown in Figure C, compared with the normal feed group, JOSD2 was significantly downregulated in the liver tissue of mice in the high-fat and high-cholesterol diet group.

[0050] Example 2: PAOA downregulates JOSD2 protein expression in hepatocytes

[0051] PAOA is a classic inducing agent in the in vitro MAFLD model. Normal hepatocytes HL7702 were treated with different concentrations of PAOA (0, 0.5, 0.75, and 1.0 mM) for 24 hours, and JOSD2 protein expression was assessed by Western blotting.

[0052] The results are as follows Figure 2 As shown in A, PAOA can downregulate JOSD2 protein expression in a concentration-dependent manner.

[0053] 2. Primary mouse hepatocytes were isolated from mouse liver tissue using collagenase digestion method and treated with different concentrations (0, 0.5, 0.75, 1.0 mM) of PAOA for 24 h. Protein immunoblotting was used to investigate the expression of JOSD2 protein.

[0054] The results are as follows Figure 2 As shown in B, PAOA can also downregulate the expression of JOSD2 protein in mouse primary hepatocytes in a concentration-dependent manner.

[0055] 3. Normal hepatocytes HL7702 were treated with 1.0 mM PAOA, and the expression of JOSD2 protein was examined by western blotting at 0 h, 6 h, 12 h, and 24 h.

[0056] The results are as follows Figure 2 As shown in Figure C, PAOA can downregulate JOSD2 protein expression in a time-dependent manner. Example 3: Liver-specific knockout of JOSD2 exacerbates the disease progression of the MAFLD model induced by a high-fat, high-cholesterol diet.

[0057] 1. JOSD2 conditional knockout mice and ALB-cre mice were hybridized to obtain JOSD2 liver-specific knockout mice. Fluorescence quantitative PCR technology was used to compare the expression of the Josd2 gene in different organs and tissues of normal mice and JOSD2 liver-specific knockout mice.

[0058] like Figure 3 As shown in A, the Josd2 gene was specifically knocked out only in mouse liver tissue, indicating that the JOSD2 liver-specific knockout model was successfully constructed.

[0059] 2. Eight-week-old normal mice and JOSD2 liver-specific knockout mice were selected and fed a normal diet or a high-fat, high-cholesterol diet for 18 weeks, with body weights monitored regularly. At the end of the experiment, orbital blood was collected from the mice, and the livers were dissected and photographed.

[0060] The results are as follows Figure 3 As shown in Figures B and C, liver-specific knockout of JOSD2 can aggravate the disease progression of MAFLD induced by a high-fat, high-cholesterol diet, mainly manifested by excessive lipid accumulation in the liver, increased body and liver weight, soft liver texture, and earthy yellow color.

[0061] Example 4: Liver-specific knockout of JOSD2 increases ALT, AST, TC, LDLC in mouse serum and TC and TG in liver tissue

[0062] 1. The blood of the mice in Example 3 was allowed to stand at room temperature for 30 minutes, and serum was obtained by centrifugation. The ALT, AST, TC and LDLC levels in the serum of the mice in each group were then detected using a kit.

[0063] The results are as follows Figure 4 As shown in AD, liver-specific knockout of JOSD2 significantly increased the levels of ALT, AST, TC and LDLC in mouse serum.

[0064] 2. Use kits to detect the TC and TG levels in the liver tissues of mice in each group.

[0065] The results are as follows Figure 4As shown in E and F, liver-specific knockout of JOSD2 can significantly increase the TC and TG contents in mouse liver tissue.

[0066] Example 5: Liver-specific knockout of JOSD2 exacerbates lipid accumulation in liver tissue, promotes the synthesis and uptake of cholesterol and fatty acids, and inhibits fatty acid β-oxidation

[0067] 1. The mouse liver tissue sections in Example 3 were stained with H&E, Oil red O, and Sirius red, respectively.

[0068] The results are as follows Figure 5 As shown in Figure A, the liver tissue of the HFHC group mice with liver-specific knockout of JOSD2 showed more obvious vacuoles, increased lipid droplet size and number, and increased collagen content, demonstrating that liver-specific knockout of JOSD2 exacerbated the progression of MAFLD induced by a high-fat, high-cholesterol diet.

[0069] 2. Fluorescence quantitative PCR technology was used to detect genes related to cholesterol and fatty acid metabolism in the liver tissues of mice in each group.

[0070] The results are as follows Figure 5 As shown in Figure 3B, liver-specific knockout of JOSD2 significantly downregulated the Cyp7a1 (Cholesterol 7α-hydroxylase) gene and upregulated the Hmgcr (3-Hydroxy-3-methylglutaryl-coenzyme A reductase) gene. The Cyp7a1 gene encodes the rate-limiting enzyme that catalyzes the decomposition of cholesterol into bile acid in the liver, while the Hmgcr gene mediates the synthesis of cholesterol. This indicates that liver-specific knockout of JOSD2 can promote cholesterol synthesis in liver tissue and inhibit its metabolism.

[0071] In addition, liver-specific knockout of JOSD2 increased the expression of fatty acid synthesis genes Fasn (Fatty acidsynthase), Scd1 (stearoyl-CoA desaturase-1), Accα (Acetyl-CoAcarboxylase alpha), Ppar-γ (Peroxisome proliferator-activated receptors gamma), and fatty acid uptake genes Fatp1 (Fatty acid transport protein 1), Fabp1 (Fatty acid binding protein 1), Cd36 (Fatty acid translocase CD36) in liver tissue, and inhibited the expression of fatty acid β-oxidation genes Acox1 (Acyl-coenzymeA oxidase 1), Mcad (Medium-chain acyl-coenzyme A dehydrogenase), Cpt-1α (Carnitine palmitoyl transferase 1alpha), indicating that liver-specific knockout of JOSD2 can promote the synthesis and uptake of fatty acids in liver tissue and inhibit fatty acid β-oxidation.

[0072] Example 6: Liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue

[0073] 1. Western blotting was used to detect the activation of the inflammatory signaling pathway IKKβ / NF-κB in the liver tissues of the mice in each group in Example 3.

[0074] The results are as follows Figure 6 As shown in Figure A, liver-specific knockout of JOSD2 significantly increased the expression of p-IKKβ (phosphorylated-IkappaB kinase beta), p-P65 (phosphorylated-NFkappaB subunitp65) and p-IKBα (phosphorylated-NF-kappaB inhibitor alpha) proteins in liver tissue.

[0075] 2. Fluorescence quantitative PCR was used to detect the expression of inflammation-related genes in the liver tissues of mice in each group.

[0076] The results are as follows Figure 6As shown in Figure 3B, liver-specific knockout of JOSD2 upregulated the expression of pro-inflammatory genes Il-1β (Interleukin-1beta), Tnfr1 (Tumor necrosis factor receptor-1), Ikkα (IkappaB kinase alpha), Il6 (Interleukin-6), and Tnfα (Tumor necrosis factor alpha), and downregulated the expression of anti-inflammatory gene Il10 (Interleukin-10), indicating that liver-specific knockout of JOSD2 promotes inflammatory response in mouse liver tissue.

[0077] Example 7: Overexpression of JOSD2 can alleviate PAOA-induced hepatocyte lipid accumulation

[0078] Vector and JOSD2 were overexpressed in HL7702 hepatocytes using lentiviral infection. The efficiency of JOSD2 overexpression was assessed by Western blotting. Cells in the Vector and JOSD2 overexpression groups were simultaneously treated with 1.0 mM PAOA for 12 hours and then stained with Oil Red O.

[0079] The results are as follows Figure 7 As shown in the results, overexpression of JOSD2 could alleviate PAOA-induced lipid accumulation in hepatocytes to a certain extent.

[0080] In summary, the present invention has confirmed for the first time the new function of the JOSD2 gene and its encoded protein in MAFLD through in vitro and in vivo experiments. By constructing a recognized high-fat, high-cholesterol diet-induced MAFLD model, it was found that JOSD2 was significantly downregulated in the liver tissue of MAFLD model mice. It was also found that liver-specific knockout of JOSD2 can increase the accumulation of lipids such as triglycerides in the liver, activate inflammatory pathways in liver tissue, thereby exacerbating the progression of the MAFLD model induced by high fat and high cholesterol, and overexpression of JOSD2 can alleviate the accumulation of hepatocyte lipids induced by PAOA. The present invention confirms that JOSD2 is a protective factor in MAFLD, and drugs that upregulate JOSD2 expression or enhance its activity can be used to treat MAFLD, providing new targets and new ideas for the clinical treatment of MAFLD and related drug development.

[0081] The above description of the embodiments is intended to facilitate understanding and application of the present invention by those skilled in the art and is not intended to limit the present invention. Those skilled in the art can readily make various modifications to these embodiments, and therefore, the present invention is not limited to the above-described embodiments. Any modifications and improvements that do not depart from the scope and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. Increase JOSD2 Use of a substance that expresses genes or enhances the function of JOSD2 protein in the preparation of a drug for treating metabolic-related fatty liver disease, characterized in that: The upregulation JOSD2 Overexpression of gene expression JOSD2 adenoviral recombinant vector or lentiviral recombinant vector; the substance that enhances the function of JOSD2 protein is JOSD2 purified protein; the metabolic-related fatty liver disease is induced by a high-fat and high-cholesterol diet, and its manifestations include liver enlargement and excessive accumulation of lipids in the liver.

2. The use according to claim 1, characterized in that Human JOSD2 The coding sequence of the gene is shown in SEQ ID NO.1, and the amino acid sequence of the encoded protein is shown in SEQ ID NO.

2.

3. The use according to claim 1, wherein Rat origin Josd2 The coding sequence of the gene is shown in SEQ ID NO.3, and the amino acid sequence of the encoded protein is shown in SEQ ID NO.

4.

4. The use according to claim 1, wherein The drug further includes a pharmaceutically acceptable carrier.

5. The use according to claim 4, characterized in that The dosage form of the drug is any one of tablets, granules, solutions, emulsions, suspensions and capsules.

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