Introduction

Fibroblast growth factor (FGF) signaling is initiated primarily through the binding of FGF ligand to FGF receptor (FGFR), a family of transmembrane tyrosine kinases, which often act in concert with co‐receptors such as Klotho proteins [1, 2]. This interaction triggers multiple downstream signaling cascades, including the rat sarcoma virus/mitogen‐activated protein kinase (RAS/MAPK), phosphatidylinositol 3‐kinase/AKT (PI3K/AKT), phospholipase C gamma (PLCγ), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Through these tightly coordinated and often cross‐regulated networks, the FGF/FGFR signaling governs fundamental cellular functions, including proliferation, differentiation, migration, survival, and metabolism [3]. Moreover, it plays an indispensable role in embryonic morphogenesis, systemic metabolic homeostasis, postnatal tissue homeostasis, and injury‐induced regenerative responses [4]. Nevertheless, dysregulation of FGF/FGFR signaling, whether caused by its loss‐of‐function or pathological hyperactivation, disrupts physiological homeostasis and is implicated in diverse pathologies, including metabolic syndromes, skeletal dysplasia, malignancies, and neurodegenerative diseases [5]. For instance, impaired FGF19/FGFR4 signaling fails to suppress hepatic bile acid (BA) synthesis, leading to intrahepatic cholestasis [6]. Conversely, oncogenic FGFR2 mutations constitutively activate downstream effectors, such as Ras–Raf–MEK–ERK, PI3K–AKT, and JAK–STAT pathways, thereby driving cholangiocarcinoma initiation and progression [7].

Currently, targeted correction of the dysregulated FGF/FGFR signaling has emerged as one of the pivotal focuses in clinical translational research [8]. Although FGF/FGFR signaling‐related intervention strategies have demonstrated breakthrough efficacy in several clinical trials, their safety and effectiveness remain challenging. For instance, the engineered FGF19 analog NGM282 significantly ameliorates hepatic steatosis and fibrosis biomarkers in nonalcoholic steatohepatitis (NASH) patients, but long‐term administration may elevate the risk of cancer [9]. Besides, FGFR inhibitors yield clear clinical benefits for tumors harboring FGFR aberrations. However, erdafitinib, a pan‐FGFR inhibitor, frequently induces dose‐limiting hyperphosphatemia in the treatment of urothelial carcinoma due to concurrent inhibition of the renal FGF23–FGFR1 axis, representing a major safety bottleneck for its clinical application [10]. Additionally, the common FGFR2 kinase domain “gatekeeper” residue V565F mutation in patients with cholangiocarcinoma renders FGFR2‐specific inhibitors ineffective [10]. Collectively, these clinical observations underscore the functional pleiotropy and regulatory complexity inherent in the FGF/FGFR signaling network. Therefore, a comprehensive understanding of the FGF/FGFR signaling is urgently necessary to develop more precise intervention strategies for targeting this signaling.

In this review, we provide an overview of FGF/FGFR signaling, its cellular and physiological functions, and diseases associated with dysregulated FGF/FGFR signaling. Furthermore, we also discuss the strategies targeting this signaling and provide new perspectives for this research field.