Abstract
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.