Advances in the Structural Basis of FGF–FGFR Protein–Protein Interactions and Biased Signaling

Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute an essential signaling system that is widely involved in development, tissue homeostasis, and metabolic regulation. In recent years, advances in cryo-electron microscopy and artificial intelligence-based structural prediction have shifted FGF–FGFR research from the traditional receptor activation paradigm toward a new framework centered on protein–protein interactions and receptor conformation-mediated signaling bias. This review summarizes the structural basis of FGF–FGFR protein interactions, with particular emphasis on the asymmetric dimer model, the distinct receptor recognition mechanisms of paracrine and endocrine FGFs, and recent progress in the receptor dimerization threshold model. We further discuss the molecular mechanisms underlying FGFR signaling bias and its application in the development of engineered FGF analogs and biased agonists, aiming to provide new theoretical insights for precision therapies for metabolic diseases.