The Use of FGF21 Analogues in MASH and MASH Cirrhosis - Metabolic Master Regulators or Liver-Specific Mechanisms? ^☆

Fibroblast growth factor 21 (FGF21) is a pleiotropic endocrine hormone that coordinates metabolic homeostasis across the liver, adipose tissue, pancreas, and central nervous system. In metabolic dysfunction-associated steatotic liver disease (MASLD) circulating FGF21 is markedly elevated, yet downstream signaling remains blunted-a state of FGF21 resistance driven by reduced β-klotho co-receptor availability and altered receptor complex function. Pharmacological FGF21 analogues were engineered to overcome unfavorable native pharmacokinetics and achieve sustained target engagement at the FGFR1c/β-klotho complex in key tissues. Liver-directed effects of FGF21 analogues encompass suppression of de novo lipogenesis and lipotoxic intermediates, attenuation of hepatocellular stress and innate immune activation, and inhibition of hepatic stellate cells. Systemically, FGF21 signaling remodels adipose tissue via an FGF21-adiponectin axis, reduces atherogenic dyslipidemia, improves insulin sensitivity, and modulates central pathways of energy expenditure and macronutrient preference. This breadth of action positions FGF21 analogues as both metabolic master regulators and liver disease therapeutics. In phase 2 clinical trials, efruxifermin, pegozafermin, and efimosfermin have demonstrated meaningful histological improvements in fibrotic MASH. In addition, efruxifermin showed histological regression of cirrhosis in a dedicated compensated cirrhosis trial. Phase 3 programs are now underway to establish effects on liver-related outcomes and mortality. FGF21 analogues appear particularly potent in inducing fibrosis regression even with modest weight loss, supporting a complementary combination strategy. Current evidence supports FGF21 pathway activation as a meaningful strategy to modify of MASH progression and potentially revert cirrhotic liver disesase.