Wong Shu Wei, Yang Yong-Yu, Chen Hui, Xie Li, Shen Xi-Zhong, Zhang Ning-Ping, Wu Jian
Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
Acta Pharmacol Sin. 2025 May;46(5):1145-1155. doi: 10.1038/s41401-024-01466-7. Epub 2025 Jan 27.
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application.
代谢功能障碍相关脂肪性肝病（MASLD）涵盖了广泛的疾病谱，从单纯性脂肪肝，发展到代谢功能障碍相关脂肪性肝炎（MASH），再到肝纤维化，进一步发展为肝硬化和肝细胞癌（HCC）。MASLD已成为一种全球性的常见疾病，全球平均患病率为25%。MASH是一个活跃阶段，当出现坏死性凋亡损伤并伴有纤维化进展时，需要进行药物干预。尽管对MASH发病机制的认识有所增加，且有新批准的resmetirom，但鉴于其复杂性和异质性病理生理学，迫切需要开发更多具有更好治疗效果和良好耐受性安全性的候选药物。随着研发中的候选药物名单不断增加，预计在这个快速发展的领域会有更多潜在候选药物成功获批，从而为不同患者群体提供不同类别的药物。在本综述中，我们更新了MASH药物治疗的进展，这些进展已完成II期或III期临床试验，并在最近两年内有可能应用于临床实践，重点关注有效性和安全性问题。对MASH治疗候选药物快速发展状况的概述，为关键问题提供了深刻见解，如分子靶点、终点选择与验证、临床试验设计与执行、与药物管理机构的互动、真实世界数据反馈以及临床应用中的进一步调整。
