Advances in FGF/FGFR Signaling: Implications for Disease and Therapy.

The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling, primarily comprising FGFs, FGFRs, and the co-receptor Klotho, regulates key physiological processes, including embryogenesis, tissue homeostasis, metabolism, and neurodevelopment. Dysregulation of FGF/FGFR signaling, whether resulting from pathological hyperactivation or loss-of-function, is implicated in multiple diseases such as skeletal dysplasia, metabolic disorders, cancers, and neurological disorders. Consequently, correction of causative FGF/FGFR signaling represents a promising clinical strategy. Despite the deepening understanding of the FGF/FGFR signaling, its clinical translation still faces challenges, including side effects and acquired resistance to pathway blockade, as well as safety concerns regarding FGF analogs. Herein, we provide an overview of FGF/FGFR signaling and summarize its cellular and physiological functions. We further delve into the relationship between aberrant (including hyperactivated or inactivated) FGF/FGFR signaling and diverse diseases. Additionally, we also discuss the strategies targeting the causative FGF/FGFR signaling, as well as offer new perspectives for optimizing these targeted therapies. Collectively, this review will contribute to the development of more precise strategies for the targeted regulation of dysregulated FGF/FGFR signaling.