Fibroblast growth factor 21 in metabolic dysfunction-associated steatotic liver disease and beyond: from bench to bedside

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease; its prevalence is increasing and projected to affect over half of the global population by 2040. Metabolic dysfunction-associated steatohepatitis (MASH), the more severe form of MASLD, is already a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Two pharmacological agents have been approved for the treatment of MASH with moderate or advanced fibrosis, but none for MASH-related cirrhosis - the stage of the disease carrying the highest risk of decompensated cirrhosis, morbidity and mortality. A positive signal from a Phase 2 study of a fibroblast growth factor 21 (FGF21) analog in patients with MASH-related cirrhosis provided hope in overcoming this significant unmet need and served as the impetus for this narrative review. FGF21 is a member of the fibroblast growth factor (FGF) superfamily with unique biology and endocrine functions, acting primarily in the liver and adipose tissue to regulate metabolic pathways involved in glucose handling, lipid oxidation, and energy expenditure. Advancements in the engineering of FGF21 molecules have provided the foundation for therapeutic agents with improved biophysical properties and manufacturing advantages. FGF21 analogs have demonstrated anti-inflammatory and anti-fibrotic effects in the liver, positioning them as promising therapeutic agents for MASH. While further studies are needed to see if an FGF21 analog can indeed be the first approved therapeutic agent for MASH-related cirrhosis, it is also worth exploring other potential applications of FGF21 beyond the liver.