Schwabe Robert F, Tacke Frank, Sugimoto Atsushi, Friedman Scott L
Department of Medicine, Columbia University, New York, NY, USA.
Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
JHEP Rep. 2025 Apr 11;7(8):101421. doi: 10.1016/j.jhepr.2025.101421. eCollection 2025 Aug.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than a quarter of the adult population worldwide. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is associated with increased risk of progression to liver fibrosis, cirrhosis and hepatocellular carcinoma, as well as cardiovascular complications. The pathogenesis of MASLD is complex and initiated by altered metabolic signalling circuits between the adipose tissue, muscle, gut and liver. Liver fibrosis is largely driven by the crosstalk of steatotic hepatocytes with macrophages and hepatic stellate cells and constitutes the primary determinant of outcomes in MASLD. Therefore, fibrosis regression is a key therapeutic goal for MASH therapies. Here, we review therapeutic strategies that directly or indirectly reduce liver fibrosis and discuss novel therapeutic concepts. Among these, the targeting of hepatocytes and metabolism have yielded fibrosis reduction in clinical trials and led to the first FDA-approved therapy for MASH. However, these therapies reduce fibrosis only in a subset of patients and have not yet shown benefits beyond the F2-F3 fibrosis stage. Direct antifibrotics and macrophage-based therapies may be more suitable for advanced stages of MASH, but are still in the developmental stage. The arsenal of therapies for MASLD is rapidly expanding and includes macrophage transplantation, hepatocyte-specific oligonucleotides, as well as CAR T cell-based therapies. Integrating these novel therapeutic concepts into stage-specific and/or combination therapies targeting divergent pathogenic mechanisms and cell types is the focus of ongoing research, which may lead to fibrosis reduction in a higher percentage of patients with MASH.
代谢功能障碍相关脂肪性肝病（MASLD）影响着全球超过四分之一的成年人口。MASLD可进展为代谢功能障碍相关脂肪性肝炎（MASH），这与进展为肝纤维化、肝硬化和肝细胞癌的风险增加以及心血管并发症相关。MASLD的发病机制复杂，由脂肪组织、肌肉、肠道和肝脏之间代谢信号通路的改变引发。肝纤维化很大程度上由脂肪变性的肝细胞与巨噬细胞和肝星状细胞的相互作用驱动，是MASLD预后的主要决定因素。因此，纤维化消退是MASH治疗的关键目标。在此，我们综述直接或间接减轻肝纤维化的治疗策略，并讨论新的治疗理念。其中，针对肝细胞和代谢的靶向治疗在临床试验中已实现纤维化减轻，并促成了首个获美国食品药品监督管理局（FDA）批准用于MASH的疗法。然而，这些疗法仅在部分患者中减轻纤维化，且尚未显示出在F2 - F3纤维化阶段以上的益处。直接抗纤维化疗法和基于巨噬细胞的疗法可能更适用于MASH的晚期阶段，但仍处于研发阶段。MASLD的治疗手段正在迅速扩展，包括巨噬细胞移植、肝细胞特异性寡核苷酸以及基于嵌合抗原受体（CAR）T细胞的疗法。将这些新的治疗理念整合到针对不同致病机制和细胞类型的阶段特异性和/或联合疗法中，是正在进行的研究重点，这可能使更高比例的MASH患者实现纤维化减轻。
