Do Albert, Zahrawi Frhaan, Mehal Wajahat Z
Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Division of Gastroenterology, University of California, Davis, Davis, USA.
Nat Rev Drug Discov. 2025 Mar;24(3):171-189. doi: 10.1038/s41573-024-01084-2. Epub 2024 Nov 28.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.
代谢功能障碍相关脂肪性肝病（MASLD）及其严重亚组代谢功能障碍相关脂肪性肝炎（MASH）已成为全球流行病，由慢性营养过剩和多种遗传易感性因素驱动。其生理后果包括肝细胞死亡、肝脏炎症和肝硬化。MASLD和MASH的首个治疗药物瑞美替昂最近已获批临床使用，并为该治疗领域注入了活力。然而，在MASH的临床研究中仍有许多有待了解的方面，如安慰剂反应的规模、最佳试验终点、纤维化逆转所需时间和副作用情况。本综述介绍了与药物开发相关的疾病发病机制方面，并讨论了两种主要治疗方法。甲状腺激素受体-β激动剂，如瑞美替昂，以及脂肪酸合酶抑制剂，作用于肝脏，使其能够在有毒的代谢环境中发挥功能。同时，胰高血糖素样肽-1类似物，如司美格鲁肽，可改善代谢，使肝脏能够自我调节，并逆转MASH的许多方面。我们还讨论了联合治疗如何可能用于治疗患者。
