Fibroblast Growth Factor 21: Mechanisms, Therapeutic Potential, and Clinical Translation in Metabolic Dysfunction

Abstract: Fibroblast growth factor 21 (FGF21) is an endocrine hepatokine that coordinates systemic energy metabolism by linking hepatic nutrient sensing with adipose and central signalling pathways. Experimental and clinical studies identify FGF21 as a critical modulator of lipid oxidation, insulin sensitivity, and inflammatory balance, processes central to the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). Endogenous FGF21 rises in response to fasting, lipotoxicity, and mitochondrial stress, yet this compensatory increase is insufficient in chronic metabolic disease, reflecting target-tissue resistance. Pharmacologic augmentation with engineered FGF21 analogues demonstrates robust reductions in hepatic fat, serum transaminases, and fibrosis biomarkers, along with improvements in triglyceride and adiponectin levels as well as liver histology. In a Phase 2b trial, efruxifermin reversed cirrhosis in 39% of participants. These agents act across the MASH cascade, mitigating lipotoxic injury, inflammation, and stellate-cell activation while favorably modifying cardiometabolic risk. FGF21 therefore represents a unifying therapeutic axis that integrates hepatic and systemic metabolic correction. Ongoing Phase 3 studies will determine whether these biochemical and histologic improvements translate into long-term clinical benefit, positioning FGF21 analogues as cornerstone therapies for metabolic disease. This review aims to synthesize current evidence on the molecular mechanisms and therapeutic potential of FGF21 in metabolic dysfunction-associated steatohepatitis. It highlights emerging clinical data on FGF21 analogues and their role in targeting key pathways of disease progression, with implications for future therapeutic strategies. Keywords: fibroblast growth factor 21, MASH, MASLD, insulin resistance, hepatic fibrosis, efruxifermin, cardiometabolic disease