线粒体丙酮酸载体抑制剂在代谢相关脂肪性肝炎治疗中的应用前景

陈心悦; 周振华

doi:10.12449/JCH260424

线粒体丙酮酸载体抑制剂在代谢相关脂肪性肝炎治疗中的应用前景

DOI: 10.12449/JCH260424

陈心悦¹,
周振华^{2, 3, , ,}

1.
上海中医药大学附属曙光医院细胞免疫实验室，上海 201203
2.
上海中医药大学附属曙光医院肝病科，上海 201203
3.
上海中医药大学附属曙光医院安徽医院肝病科，合肥 230031

基金项目:

国家中医药管理局高水平中医药重点学科建设项目（中医肝胆病学） (zyyzdxk-2023060);

安徽省自然科学基金 (2308085MH293);

安徽省高校科学研究重大项目 (2023AH040098);

安徽省卫生健康科研重点项目 (AHWJ2023A10035)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：陈心悦负责撰写论文，绘制图片；周振华拟定写作思路并最后定稿。

详细信息

通信作者:
周振华， Jinghua1220@163.com （ORCID： 0000-0002-5639-3857）

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出版历程
- 收稿日期: 2025-07-10
- 录用日期: 2025-10-27
- 出版日期: 2026-04-25

Application prospects of mitochondrial pyruvate carrier inhibitors in treatment of metabolic dysfunction-associated steatohepatitis

Xinyue CHEN¹,
Zhenhua ZHOU^{2, 3
, ,
,}

1.
Cellular Immunology Laboratory，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
2.
Department of Hepatology，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
3.
Department of Hepatology，Anhui Hospital，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Hefei 230031，China

Research funding:

Key Discipline Construction Project of High-Level Traditional Chinese Medicine of the State Administration of Traditional Chinese Medicine （Traditional Chinese Medicine Hepatobiliary Disease） (zyyzdxk-2023060);

Natural Science Foundation of Anhui Province (2308085MH293);

Major Project of Scientific Research for Universities in Anhui Province (2023AH040098);

Key Project of Scientific Research for Health and Wellness in Anhui Province (AHWJ2023A10035)

More Information

Corresponding author: ZHOU Zhenhua， Jinghua1220@163.com （ORCID： 0000-0002-5639-3857）

摘要

摘要: 代谢相关脂肪性肝炎（MASH）是一种复杂的肝脏疾病，其病理特征是肝脏中脂肪异常累积，伴随炎症和肝细胞损伤，可逐渐发展为肝纤维化、肝硬化甚至肝癌。MASH的发病机制复杂，涉及胰岛素抵抗、脂肪从头合成（DNL）增加、氧化应激和线粒体功能障碍等多个环节。近年来，线粒体丙酮酸载体（MPC）作为调控脂质代谢的关键分子靶点备受关注。本文系统综述了MPC在MASH中的作用机制，重点探讨抑制MPC表达如何通过减少DNL生成并调控腺苷一磷酸活化的蛋白质激酶-乙酰辅酶A羧化酶等信号通路来调节脂质合成代谢，最终改善肝脏炎症。此外，本文展望了MPC抑制剂在MASH治疗中的潜在应用前景，以期为未来治疗MASH的临床研究提供新的思路。
- 代谢相关脂肪性肝炎 /
- 线粒体丙酮酸载体 /
- 治疗学
Abstract: Metabolic dysfunction-associated steatohepatitis （MASH） is a complex liver disease characterized by abnormal fat accumulation in the liver， accompanied by inflammation and hepatocyte injury， and it can gradually progress to liver fibrosis， liver cirrhosis， and even hepatocellular carcinoma. MASH has a complex pathogenesis involving multiple links such as insulin resistance， de novo lipogenesis （DNL）， oxidative stress， and mitochondrial dysfunction. In recent years， mitochondrial pyruvate carrier （MPC） has attracted wide attention as a key molecular target for regulating lipid metabolism. This article systematically reviews the mechanism of action of MPC in MASH， with a focus on how inhibiting MPC expression regulates lipid synthesis and metabolism by reducing DNL production and modulating signaling pathways such as AMPK-ACC， thereby improving liver inflammation. In addition， this article discusses the potential application prospects of MPC inhibitors in MASH treatment， in order to provide new ideas for future clinical research on MASH management.
- Metabolic Dysfunction-Associated Steatohepatitis /
- Mitochondrial Pyruvate Carrier /
- Therapeutics

HTML全文

注： IR，胰岛素抵抗；DNL，脂肪从头合成；ACC，乙酰辅酶A羧化酶；FASN，脂肪酸合成酶；MPC，线粒体丙酮酸载体；ChREBP，碳水化合物反应元件结合蛋白；α-SMA，α-平滑肌肌动蛋白；ATP，腺苷三磷酸；AMP，腺苷一磷酸；AMPK，AMP活化的蛋白质激酶；mTORC1，雷帕霉素靶蛋白复合物1；SREBP-1c，甾醇调节元件结合蛋白-1c；Malonyl-CoA，丙二酰辅酶A；CPT1A，肉毒碱棕榈酰转移酶1A；MASH，代谢相关脂肪性肝炎。

图 1 MPC抑制剂治疗MASH的分子机制

Figure 1. The molecular mechanism of MPC inhibitors in treating MASH

下载: 全尺寸图片幻灯片

参考文献(36)

[1]	DO A, ZAHRAWI F, MEHAL WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis(MASH)[J]. Nat Rev Drug Discov, 2025, 24( 3): 171- 189. DOI: 10.1038/s41573-024-01084-2.
[2]	MARTIN OP, WALLACE MS, OETHEIMER C, et al. Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis[J]. Nat Immunol, 2025, 26( 9): 1596- 1611. DOI: 10.1038/s41590-025-02255-y.
[3]	MIAO L, TARGHER G, BYRNE CD, et al. Current status and future trends of the global burden of MASLD[J]. Trends Endocrinol Metab, 2024, 35( 8): 697- 707. DOI: 10.1016/j.tem.2024.02.007.
[4]	YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64( 1): 73- 84. DOI: 10.1002/hep.28431.
[5]	Committee of Hepatology, Chinese Research Hospital Association; Fatty Liver Expert Committee, Chinese Medical Doctor Association; National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, et al. Expert recommendations on standardized diagnosis and treatment for fatty liver disease(2019 revised edition)[J]. J Clin Hepatol, 2019, 35( 11): 2426- 2430. DOI: 10.3969/j.issn.1001-5256.2019.11.007. 中国研究型医院学会肝病专业委员会, 中国医师协会脂肪性肝病专家委员会, 中华医学会肝病学分会脂肪肝与酒精性肝病学组, 等. 脂肪性肝病诊疗规范化的专家建议(2019年修订版)[J]. 临床肝胆病杂志, 2019, 35( 11): 2426- 2430. DOI: 10.3969/j.issn.1001-5256.2019.11.007.
[6]	National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association; Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: A 2018 update[J]. J Clin Hepatol, 2018, 34( 5): 947- 957. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34( 5): 947- 957. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[7]	FU JT, LIU J, WU WB, et al. Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis[J]. J Hepatol, 2024, 81( 3): 389- 403. DOI: 10.1016/j.jhep.2024.04.009.
[8]	YANG B, ZHANG R. Progress on the treatment of metabolic associated fatty liver disease[J/CD]. Chin J Liver Dis(Electronic Version), 2024, 16( 4): 25- 30. DOI: 10.3969/j.issn.1674-7380.2024.04.004. 杨彬, 张瑞. 代谢相关脂肪性肝病治疗进展[J/CD]. 中国肝脏病杂志(电子版), 2024, 16( 4): 25- 30. DOI: 10.3969/j.issn.1674-7380.2024.04.004.
[9]	PORTINCASA P, BAFFY G. Metabolic dysfunction-associated steatotic liver disease: Evolution of the final terminology[J]. Eur J Intern Med, 2024, 124: 35- 39. DOI: 10.1016/j.ejim.2024.04.013.
[10]	YU YF, BAI LN, JIAO JW, et al. Research progress in traditional Chinese medicine in the prevention and treatment of non-alcoholic steatohepatitis based on mitochondrial regulation mechanism[J]. J Changchun Univ Chin Med, 2025, 41( 4): 456- 460. DOI: 10.13463/j.cnki.cczyy.2025.04.022. 于云飞, 白洛宁, 焦靖雯, 等. 基于线粒体调控机制对中药防治NASH的研究进展[J]. 长春中医药大学学报, 2025, 41( 4): 456- 460. DOI: 10.13463/j.cnki.cczyy.2025.04.022.
[11]	FRANCQUE SM, MARCHESINI G, KAUTZ A, et al. Non-alcoholic fatty liver disease: A patient guideline[J]. JHEP Rep, 2021, 3( 5): 100322. DOI: 10.1016/j.jhepr.2021.100322.
[12]	LLOVET JM, PINYOL R, KELLEY RK, et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma[J]. Nat Cancer, 2022, 3( 4): 386- 401. DOI: 10.1038/s43018-022-00357-2.
[13]	LEI SS, PENG WH, WU LL, et al. Chaihu Shugan powder restores fatty acid synthesis to alleviate insulin resistance in metabolic syndrome by regulating the LXRα/SREBP-1 signaling pathway[J]. Front Pharmacol, 2024, 15: 1442279. DOI: 10.3389/fphar.2024.1442279.
[14]	YILMAZ M, CLAIBORN KC, HOTAMISLIGIL GS. De novo lipogenesis products and endogenous lipokines[J]. Diabetes, 2016, 65( 7): 1800- 1807. DOI: 10.2337/db16-0251.
[15]	FROMENTY B, RODEN M. Mitochondrial alterations in fatty liver diseases[J]. J Hepatol, 2023, 78( 2): 415- 429. DOI: 10.1016/j.jhep.2022.09.020.
[16]	LIAO YL, CHEN QS, LIU L, et al. Amino acid is a major carbon source for hepatic lipogenesis[J]. Cell Metab, 2024, 36( 11): 2437- 2448. DOI: 10.1016/j.cmet.2024.10.001.
[17]	ZHOU J, MASSEY S, STORY D, et al. Metformin: An old drug with new applications[J]. Int J Mol Sci, 2018, 19( 10): 2863. DOI: 10.3390/ijms19102863.
[18]	ORE A, AKINLOYE OA. Oxidative stress and antioxidant biomarkers in clinical and experimental models of non-alcoholic fatty liver disease[J]. Medicina, 2019, 55( 2): 26. DOI: 10.3390/medicina55020026.
[19]	SIMÕES ICM, AMORIM R, TEIXEIRA J, et al. The alterations of mitochondrial function during NAFLD progression-an independent effect of mitochondrial ROS production[J]. Int J Mol Sci, 2021, 22( 13): 6848. DOI: 10.3390/ijms22136848.
[20]	MA YQ, LEE G, HEO SY, et al. Oxidative stress is a key modulator in the development of nonalcoholic fatty liver disease[J]. Antioxidants, 2021, 11( 1): 91. DOI: 10.3390/antiox11010091.
[21]	PORTINCASA P, KHALIL M, MAHDI L, et al. Metabolic dysfunction-associated steatotic liver disease: From pathogenesis to current therapeutic options[J]. Int J Mol Sci, 2024, 25( 11): 5640. DOI: 10.3390/ijms25115640.
[22]	ZOU SY, LANG TQ, ZHANG BY, et al. Fatty acid oxidation alleviates the energy deficiency caused by the loss of MPC1 in MPC1^+/- mice[J]. Biochem Biophys Res Commun, 2018, 495( 1): 1008- 1013. DOI: 10.1016/j.bbrc.2017.11.134.
[23]	GRAY LR, SULTANA MR, RAUCKHORST AJ, et al. Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis[J]. Cell Metab, 2015, 22( 4): 669- 681. DOI: 10.1016/j.cmet.2015.07.027.
[24]	LIU CL, WU JJ, ZHU J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81[J]. J Biol Chem, 2009, 284( 5): 2811- 2822. DOI: 10.1074/jbc.M806409200.
[25]	RAUCKHORST AJ, GRAY LR, SHELDON RD, et al. The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity[J]. Mol Metab, 2017, 6( 11): 1468- 1479. DOI: 10.1016/j.molmet.2017.09.002.
[26]	GAO RX, LI Y, XU ZM, et al. Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease[J]. Hepatology, 2023, 78( 6): 1800- 1815. DOI: 10.1097/HEP.0000000000000279.
[27]	RAUCKHORST AJ, SHELDON RD, PAPE DJ, et al. A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones[J]. Cell Metab, 2025, 37( 1): 255- 273. DOI: 10.1016/j.cmet.2024.10.013.
[28]	GUO ZW, SONG T, WANG ZQ, et al. The chaperone Hsp70 is a BH3 receptor activated by the pro-apoptotic Bim to stabilize anti-apoptotic clients[J]. J Biol Chem, 2020, 295( 37): 12900- 12909. DOI: 10.1074/jbc.RA120.013364.
[29]	GOEDEKE L, BATES J, VATNER DF, et al. Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents[J]. Hepatology, 2018, 68( 6): 2197- 2211. DOI: 10.1002/hep.30097.
[30]	MCCOMMIS KS, HODGES WT, BRUNT EM, et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis[J]. Hepatology, 2017, 65( 5): 1543- 1556. DOI: 10.1002/hep.29025.
[31]	LI ZY, TIAN Z, SHI XL, et al. Adipose tissue-derived PRXL2A suppresses hepatic lipogenesis in a study with male mice[J]. Nat Commun, 2025, 16: 6567. DOI: 10.1038/s41467-025-61963-z.
[32]	ZHOU YX, WANG GF, LIU LL, et al. Cellular crosstalk mediated by Meteorin-like regulating hepatic stellate cell activation during hepatic fibrosis[J]. Cell Death Dis, 2025, 16( 1): 405. DOI: 10.1038/s41419-025-07734-6.
[33]	HABIBI M, FERGUSON D, EICHLER SJ, et al. Mitochondrial pyruvate carrier inhibition attenuates hepatic stellate cell activation and liver injury in a mouse model of metabolic dysfunction-associated steatotic liver disease[J]. bioRxiv[Preprint], 2023. DOI: 10.1101/2023.02.13.528384.
[34]	YIEW NKH, FINCK BN. The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism[J]. Am J Physiol Endocrinol Metab, 2022, 323( 1): E33- E52. DOI: 10.1152/ajpendo.00074.2022.
[35]	TAVOULARI S, SICHROVSKY M, KUNJI ERS. Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition[J]. Acta Physiol, 2023, 238( 4): e14016. DOI: 10.1111/apha.14016.
[36]	HARRISON SA, ALKHOURI N, DAVISON BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study[J]. J Hepatol, 2020, 72( 4): 613- 626. DOI: 10.1016/j.jhep.2019.10.023.