In recent years, the rising prevalence of obesity and type 2 diabetes has made metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive stage, metabolic dysfunction-associated steatohepatitis (MASH), a growing global public health burden. Although several candidate drugs targeting MASLD/MASH have entered clinical trials, their mechanisms of action have long remained unclear. On May 13, 2025, a pivotal study published in Cell Metabolism elucidated for the first time the mechanism by which FGF21 (Fibroblast Growth Factor 21) reverses MASH through coordinated actions in the central nervous system (CNS) and liver.
Led by Professor Matthew J. Potthoff, the study utilized two diet-induced MASH mouse models (FPC-MASH and GAN diet) and assessed the effects of continuous exogenous FGF21 infusion on lipid metabolism and liver fibrosis. The findings revealed that FGF21 significantly reduces liver triglyceride and cholesterol levels, ameliorating steatosis and liver fibrosis. The effect on triglycerides is primarily mediated through the CNS, while cholesterol regulation depends on direct action on hepatocytes.
Figure 1. Title and Journal Information
FGF21 (Fibroblast Growth Factor 21) is an endocrine hormone secreted by the liver and a member of the fibroblast growth factor (FGF) family. Unlike most FGFs, which act locally, FGF21 exhibits hormone-like properties, regulating metabolic states in multiple organs via the bloodstream, earning it the designation of a “metabolic hormone.” Due to its multifaceted benefits in improving insulin sensitivity, reducing blood lipids, and regulating appetite and body weight, several long-acting FGF21-based drugs (e.g., Efruxifermin and Pegozafermin) have advanced to phase III clinical trials, demonstrating significant potential in improving MASH and liver fibrosis. FGF21 is thus considered a key candidate target for next-generation metabolic disease therapies.
Figure 2. Experimental Design and Principles
This study unveiled the critical mechanism by which FGF21 reverses MASH through coordinated actions in the CNS and hepatocytes, reinforcing its status as a therapeutic target for next-generation metabolic disease treatments. Future research will explore whether similar mechanisms exist in humans and aim to develop more precise indications and treatment strategies for FGF21-based drugs with varying structures.
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