Abstract Fibroblast growth factors (FGFs) form an evolutionarily conserved signaling system that governs embryonic patterning, tissue regeneration, and systemic metabolic homeostasis. Through coordinated interactions with fibroblast growth factor receptors (FGFRs) and context-specific cofactors, FGF signaling enables precise spatial and temporal control of cellular fate and interorgan communication. While canonical FGFs coordinate local tissue dynamics, endocrine members like FGF19, FGF21, and FGF23 function as systemic hormones to regulate bile acid, glucose, and phosphate metabolism. Despite rapid advances in understanding these pathways, a unified framework that integrates their structural diversity, complex regulatory mechanisms, and the contrasting roles they play in health and disease remains fragmented. In this review, we systematically summarize the classification, structural features, and receptor specificity of the FGF family, with particular emphasis on canonical, endocrine, and intracellular FGFs. We delineate canonical and non-canonical FGF signaling pathways and their multilayered regulation by heparan sulfate proteoglycans, Klotho coreceptors, and intracellular feedback mechanisms. Furthermore, we integrate emerging insights into the roles of FGFs in organ development, tissue repair, metabolic regulation, and disease pathogenesis. A core translational insight emphasized throughout is the therapeutic duality of targeting the FGF axis: harnessing FGF agonism for tissue regeneration and metabolic regulation, versus employing FGF antagonism to block oncogenic signaling in cancer. By providing an integrated and mechanistic overview, this review clarifies key knowledge gaps and establishes a conceptual foundation for future FGF-based therapeutic innovation.
Liu et al. (Sun,) studied this question.