FGF21 emerges as central endocrine hormone in metabolic regulation, overcoming resistance with optimized analogs

Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes represent significant global health challenges, often characterized by insulin resistance, hepatic steatosis, and chronic inflammation. Current standard-of-care treatments frequently fall short in fully addressing the complex pathophysiology. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that plays a crucial role in metabolic regulation, enhancing insulin sensitivity and protecting pancreatic β-cells, making it a compelling target for novel therapeutic strategies.

This comprehensive review synthesizes current literature on FGF21 biology, focusing on its role in diabetes and metabolic dysfunction. Researchers systematically analyzed studies detailing FGF21 signaling pathways, its regulatory networks, and its impact on glucose and lipid homeostasis, inflammation, mitochondrial health, and autophagy. The review also critically evaluates the phenomenon of FGF21 resistance and explores the development of pharmacologically optimized FGF21 analogs and multi-agonists designed to enhance therapeutic efficacy.

The review highlights FGF21 as a pleiotropic endocrine hormone, primarily from the liver, acting via FGFR1c and its co-receptor β-Klotho across adipose tissue, skeletal muscle, pancreas, and the central nervous system. In diabetes mellitus, FGF21 improves insulin sensitivity, boosts adiponectin secretion, mitigates hepatic steatosis, and protects pancreatic β-cells from oxidative and ER stress. These benefits are mediated through key molecular pathways, including AMPK, SIRT1, PGC-1α, and mTOR signaling.

Despite elevated circulating FGF21 levels in obesity and type 2 diabetes, biological responsiveness is diminished—a phenomenon termed FGF21 resistance, characterized by impaired receptor expression, inflammatory signaling interference, and downstream signaling deficits. The review emphasizes the development of optimized FGF21 analogs and multi-agonists to overcome this resistance and improve therapeutic potential.