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

Area of Science:

• Endocrinology
• Metabolic disease research
• Hepatology

Background:

• Fibroblast growth factor 21 (FGF21) is a key regulator of energy metabolism, impacting lipid oxidation and insulin sensitivity.
• FGF21 levels increase during fasting but are insufficient in chronic metabolic diseases like MASH.
• MASH pathogenesis involves hepatic fat accumulation, inflammation, and fibrosis, processes modulated by FGF21.

Purpose of the Study:

• To review the molecular mechanisms and therapeutic potential of FGF21 in MASH.
• To synthesize current evidence on FGF21 analogues for MASH treatment.
• To highlight FGF21's role in targeting key disease pathways.

Main Methods:

• Review of experimental and clinical studies on FGF21 and MASH.
• Analysis of data from Phase 2b and ongoing Phase 3 trials of FGF21 analogues (e.g., efruxifermin).
• Examination of FGF21's effects on hepatic fat, inflammation, fibrosis, and cardiometabolic risk factors.

Main Results:

• Engineered FGF21 analogues reduce hepatic fat, transaminases, and fibrosis biomarkers.
• Improvements observed in triglyceride levels, adiponectin, and liver histology.
• Efruxifermin demonstrated cirrhosis reversal in 39% of participants in a Phase 2b trial.

Conclusions:

• FGF21 analogues target multiple MASH pathways, mitigating injury and inflammation.
• These agents offer a unified therapeutic approach for hepatic and systemic metabolic correction.
• Ongoing Phase 3 studies will confirm long-term clinical benefits, potentially establishing FGF21 analogues as cornerstone MASH therapies.