Review Article

New advances in novel pharmacotherapeutic candidates for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) between 2022 and 2024

Shu Wei Wong1, Yong-yu Yang1, Hui Chen1, Li Xie1, Xi-zhong Shen2,3, Ning-ping Zhang2,3, Jian Wu1,2,3
1 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
2 Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
3 Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
Correspondence to: Ning-ping Zhang: zhang.ningping@zs-hospital.sh.cn, Jian Wu: zhang.ningping@zs-hospital.sh.cn,
DOI: 10.1038/s41401-024-01466-7
Received: 14 September 2024
Accepted: 18 December 2024
Advance online: 27 January 2025

Abstract

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.
Keywords: metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; thyroid hormone receptor beta (THR-β); glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide receptor (GIPR); fibroblast gr

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