Fibroblast growth factor 23 (FGF23) is a bone-derived hormone and growth factor that plays a central role in phosphate and mineral homeostasis. Beyond its classical endocrine actions on the kidney, accumulating evidence indicates that FGF23 exerts broad paracrine and systemic effects that extend to metabolism, inflammation, cardiovascular function and cancer biology. FGF23 production is tightly regulated at the transcriptional and post-translational levels in osteocytes and osteoblasts, resulting in the release of either intact bioactive FGF23 or cleaved fragments with distinct biological properties. Canonical FGF23 signalling requires fibroblast growth factor receptors in complex with the co-receptor α-Klotho, although α-Klotho-independent pathways have been described in several tissues. This review provides a comprehensive overview of FGF23 biology, focusing on its regulation, processing and signalling mechanisms, and integrating current knowledge of its paracrine and endocrine actions across multiple organ systems. We discuss the role of FGF23 in bone mineralisation, phosphocalcium metabolism and energy homeostasis, as well as its involvement in inflammatory states, anaemia, cardiovascular disease, chronic kidney disease, cancer and nervous system function. Experimental and clinical evidence supporting both adaptive and maladaptive roles of FGF23 in health and disease is critically examined. Overall, FGF23 emerges as a multifunctional growth factor and hormone that links bone to systemic metabolic and inflammatory networks. Understanding the context-dependent actions of FGF23 may provide novel insights into disease mechanisms and identify new opportunities for therapeutic intervention. • FGF23 integrates bone-derived signalling with systemic metabolic regulation • Post-translational processing critically shapes FGF23 signalling outcomes • FGF23 exerts paracrine effects on bone mineralisation and osteocyte function • Endocrine FGF23 links mineral metabolism to inflammation and energy balance • Dysregulated FGF23 contributes to cardiovascular, renal and systemic disease
Crespo-Golmar et al. (Sun,) studied this question.