Fibroblast growth factor receptor 1c signaling pathway (FGFR1c pathway)

The Fibroblast growth factor receptor 1c (FGFR1c) signaling pathway is a critical regulator of systemic metabolism and cellular homeostasis. In the presence of the co-receptor beta-Klotho (KLB), FGFR1c is the primary mediator for the endocrine hormone FGF21, which enhances insulin sensitivity, promotes lipid oxidation, and reduces hepatic fat accumulation. This pathway has become a major therapeutic focus for metabolic disorders, particularly metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes, where FGF21 analogs or FGFR1c/KLB bispecific antibodies are used to reverse steatosis and fibrosis. Beyond metabolism, dysregulation of FGFR1c signaling is implicated in various cancers, where it can drive tumor cell proliferation and angiogenesis. Consequently, the pathway is targeted both by agonists for metabolic health and by small-molecule tyrosine kinase inhibitors for oncology, though therapeutic use must balance metabolic benefits against potential risks such as bone density loss and cardiovascular effects.

Other names

FGFR1-IIIcFGF21-FGFR1c-KLB complexFibroblast growth factor receptor 1 isoform cFGF21 signaling axis

Agonism of the FGFR1c/beta-Klotho complex to mimic the metabolic effects of FGF21, or tyrosine kinase inhibition to block oncogenic signaling.