Dysregulated FGF/FGFR Signaling‐Related Diseases

Under physiological conditions, the transmission of FGF/FGFR signal is precisely regulated. However, multiple factors such as gain or loss‐of‐function mutations in receptors or ligands, gene amplification, the formation of autocrine/paracrine feedback loops, and overexpression of ligands can lead to abnormal FGF/FGFR signaling. Such dysregulation, whether manifesting as overactivation or attenuation, may disrupt the systemic homeostasis and contributes to the pathogenesis of multiple diseases (Figure 5). For instance, activating mutations in FGFR serve as key drivers of various cancers, including HCC, cholangiocarcinoma, and bladder cancer [8]. Besides, gain‐of‐function mutations in FGF23 cause autosomal dominant hypo‐phosphatemic rickets [196], whereas inactivating mutations in FGFR3 result in excessive bone growth [197].

FIGURE 5: The association between dysregulated FGF/FGFR signaling and multiple human diseases. Aberrant regulation of FGF/FGFR signaling, including sustained overactivation and pathological attenuation, is closely correlated with the occurrence and progression of a wide range of human disorders. Representative diseases corresponding to these two abnormal signaling patterns are illustrated separately as follows. On the left side are disorders associated with sustained excessive activation of FGF/FGFR signaling: Upregulated FGF19 promotes cancer stem cell self‐renewal, immune evasion, and malignant proliferation, thus driving tumor development. Elevated FGF23 after kidney injury acts on cardiomyocyte FGFR4, induces activation of the calcineurin/NFAT pathway, and leads to left ventricular hypertrophy. Increased FGF2 in the intestinal immune microenvironment activates the FGFR/MAPK/ERK and NF‐κB cascades, upregulates pro‐inflammatory cytokines, including IL‐6 and TNF‐α, and aggravates inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Gain‐of‐function mutations in FGFR3 inhibit chondrocyte proliferation and differentiation, resulting in achondroplasia. On the right side are diseases related to attenuated FGF/FGFR signaling: Downregulated FGF1/2/7 mediates neuronal injury and contributes to the progression of Alzheimer's disease. Insufficient FGF2 secretion inhibits angiogenesis, fibroblast proliferation, and keratinocyte migration, resulting in chronic refractory wounds. Impaired FGF19/FGFR4 signaling disrupts bile acid and fatty acid metabolism, increases reactive oxygen species production, and induces cholestasis and MASH. In addition, FGFR3 gene mutations cause insufficient signaling, trigger abnormal cell proliferation and differentiation, and ultimately result in CATSHL syndrome. Created with Biorender.com. ACH, achondroplasia; BA, bile acid; CD, Crohn's disease; FAO, fatty acid oxidation; LVH, left ventricular hypertrophy; ROS, reactive oxygen species; UC, ulcerative colitis.

Sustained Hyperactivated FGF/FGFR Signaling

When FGF/FGFR signaling is hyperactivated, the continuous enhancement of the signal can lead to uncontrolled cell proliferation, abnormal differentiation, increased anti‐apoptotic ability, and so forth, which, in turn, triggers a range of pathological processes, such as metabolic disorders and tumorigenesis.

Diseases of the Skeletal System

ACH is the most common form of hereditary dwarfism in humans, characterized by short limbs, macrocephaly with frontal bossing, lumbar lordosis, and other skeletal deformities [198]. The underlying pathogenic mechanism involves a missense mutation at the 1138th nucleotide of the FGFR3 gene, where guanine (G) is replaced by adenine (A), resulting in the substitution of a highly conserved glycine residue at position 380 in the TMD of the encoded protein with arginine (G380R) [199]. This mutation enables FGFR3 to form stable dimers spontaneously in the absence of ligands, leading to constitutive activation of the kinase domain [200]. Consequently, it hinders longitudinal bone growth through downstream signaling pathways. First, excessive activation of the MAPK/ERK pathway upregulates p21 expression, which, in turn, arrests chondrocytes in the proliferative zone at the G1 phase of the cell cycle, thereby markedly suppressing their proliferation capacity [81, 201]. Secondly, the mutation disrupts the established Indian hedgehog‐parathyroid hormone‐related protein (IHH‐PTHrP) negative feedback loop within the growth plate, leading to premature hypertrophic differentiation of chondrocytes and dysregulation of their differentiation process [202]. Third, the mutant receptor further intensifies cell cycle arrest through the FRS2‐STAT1 signaling axis [203]. Additionally, mutant FGFR3 also affects the structure and function of primary cilia in chondrocytes, interfering with Hedgehog and other signaling pathways [204, 205]. Collectively, these alterations impede the longitudinal growth of long bones, leading to short‐limbed dwarfism. In contrast, more severe FGFR3 mutations (e.g., R248C, K650M/E) that cause lethal dysplasia completely disrupt growth plate architecture and lead to fatal thoracic dysplasia [206, 207].

Craniosynostosis syndrome encompasses a group of congenital craniofacial malformations caused by premature closure of cranial sutures. It is characterized by abnormal head shape, elevated intracranial pressure, midface hypoplasia, exophthalmos and may be accompanied by syndactyly, intellectual disability, and other clinical manifestations [208]. This syndrome is primarily caused by gain‐of‐function point mutations in the FGFR1, FGFR2, or FGFR3 genes [209]. Within the context of Apert syndrome, the S252W or P253R mutations in the FGFR2 gene markedly enhance the receptor's affinity for its ligands and enable aberrant binding to non‐classical ligands [77, 210, 211]. This abnormal ligand–receptor interaction leads to continuous and excessive activation of downstream RAS–MAPK/ERK and PI3K–AKT signaling pathways [212]. A salient consequence of such pathway hyperactivity is the transcriptional upregulation of Runx2 and Osterix, which function as master regulators of osteogenic commitment. This, in turn, accelerates the differentiation of osteoprogenitor cells and promotes pathological matrix mineralization, ultimately resulting in premature fusion of cranial sutures [78]. Mutations in different FGFR genes and at distinct sites give rise to varying patterns of cranial suture fusion and associated clinical features. For example, the P252R mutation in FGFR1 causes Pfeiffer syndrome, whereas the P250R and A391E mutations in FGFR3 are associated with Muenke syndrome and Crouzon syndrome with acanthosis nigricans, respectively. Collectively, these distinct mutations constitute a complex disease spectrum [213, 214].

OA is the most common degenerative joint disease, characterized by progressive destruction of articular cartilage, subchondral bone sclerosis, osteophyte formation, and synovial inflammation [215]. Studies have demonstrated the FGF/FGFR signaling exerts complex bidirectional regulation in OA. In diseased joints, damaged chondrocytes, activated synoviocytes, and inflammatory cells produce substantial amount of FGF2, which acts through FGFR1, highly expressed on chondrocytes, and in concert with pro‐inflammatory factors such as IL‐1β to activate the MAPK/ERK and PKCδ pathways. This concerted activation, in turn, transcriptionally upregulates MMP‐13 as well as disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)‐4/5, which mediate the degradation of Type II collagen and aggrecan, the primary structural constituents of cartilage ECM [216]. Conversely, endogenous FGF2 functions as a chondroprotective factor in the destabilization of the medial meniscus (DMM) mouse model of OA, inhibiting ADAMTS‐5 expression and mitigating cartilage degeneration [217]. In contrast, FGF18 mainly transmits anabolic signals via binding to FGFR3 on chondrocytes, promoting the synthesis of proteoglycans and Type II collagen while inhibiting chondrocyte apoptosis [218]. On the basis of this mechanism, recombinant human FGF18 (Sprifermin) has been demonstrated in clinical trials to increase the thickness of knee articular cartilage and slow cartilage loss [219]. Collectively, an imbalance between FGF2‐driven catabolism and FGF18‐driven anabolism is the key driver of the progression of OA.

Metabolic and Endocrine Diseases

X‐linked hypophosphatemic rickets (XLH) is the most common hereditary hypophosphatemic rickets, characterized by rickets in childhood and osteomalacia in adulthood, which is accompanied by hypophosphatemia, renal phosphate wasting, and inappropriately normal or low levels of 1,25(OH)2D3 [220]. In contrast, tumor‐induced osteomalacia (TIO) is an acquired disorder that typically presents in adults with bone pain, muscle weakness, fractures, and hypophosphatemia, and the symptoms are usually reversible after the surgical removal of the FGF23‐secreting tumor [221]. The core pathophysiological feature underlying both diseases is the abnormally elevated level of FGF23. In XLH, inactivating mutations in the phosphate‐regulating endopeptidase homolog X‐linked (PHEX) gene result in impaired degradation of FGF23, leading to elevated circulating concentrations of the phosphatonin [222]. However, benign mesenchymal tumors ectopically produce excessive FGF23 in TIO, resulting in elevated FGF23 levels [223]. Excessive FGF23 mainly binds to the FGFR–Klotho receptor complex located on the apical membrane of renal proximal tubule cells, which activates intracellular signaling cascades that result in the downregulation of sodium‐dependent phosphate transporters NaPi‐IIa and NaPi‐IIc, leading to impaired phosphorus reabsorption. This leads to renal phosphate wasting and hypophosphatemia. Concomitantly, excessive FGF23 inhibits CYP27B1 activity, reducing the synthesis of 1,25(OH)2D3 and further aggravating the disorder of bone mineralization [224]. Given this pathogenic mechanism, monoclonal antibodies (mAbs) targeting FGF23 have been developed for clinical treatment against XLH [225].

Inflammatory and Autoimmune Diseases

Inflammatory bowel disease (IBD) encompasses a group of chronic and recurrent gastrointestinal inflammatory disorders, characterized by aberrant activation of the intestinal mucosal immune system, leading to inflammation, ulceration, and abnormal repair [226]. Of note, FGF2 level is significantly elevated in the inflamed intestinal mucosa and serum of patients with IBD [227]. Studies have shown a synergistic interaction between FGF2 and IL‐17. Specifically, the upregulation of inflammation‐related genes in intestinal epithelial cells and immune cells is driven by IL‐17 through the activation of the NF‐κB and MAPK signaling cascades. Concurrently, FGF2 activates the MAPK signaling cascade upon binding to FGFR receptors. Together, in coordination with IL‐17‐driven signals, this cascade promotes the expression of pro‐inflammatory cytokines, including IL‐6 and TNF‐α, with the net effect of amplifying local intestinal inflammation. Within this pro‐inflammatory milieu, FGF2 also upregulates tight junction proteins and repairs the intestinal epithelial barrier, suggesting a compensatory protective response mounted by the host in the inflammatory microenvironment [192, 228]. Consequently, targeting FGF2 signaling may represent a potential strategy for regulating inflammation related to the Th17 pathway.

RA is a chronic systemic autoimmune disease characterized by symmetrical and erosive polyarthritis, with the hallmark feature being destruction of articular cartilage and bone resulting from proliferative synovial inflammation [229]. In the synovial tissue of RA, FGF2 level is significantly elevated, primarily due to production by activated macrophages, endothelial cells, and synovial fibroblasts [230]. Within the joint microenvironment, FGF2 synergizes with IL‐17 to engage the ERK signaling axis, a collaborative interaction that robustly induces expression of multiple pro‐inflammatory mediators and chemokines in synovial fibroblasts, including IL‐6, keratinocyte chemoattractant (KC), CXCL2, and cyclooxygenase‐2 (COX‐2) in synovial fibroblasts. The consequence is the amplification of synovial inflammation and the acceleration of joint structural damage [192].

Psoriasis is a prevalent, chronic, and relapsing inflammatory dermatosis pathologically featured with hyperproliferation and aberrant differentiation of epidermal keratinocytes, dermal capillary angiogenesis, and dense inflammatory cell infiltration [231]. Elevated expression of FGF2 has been consistently observed in lesional skin of patients with psoriasis [232]. Analogous to its role in RA, FGF2 acts synergistically with IL‐17 to drive keratinocyte dysregulation, manifesting as both uncontrolled proliferation and enhanced production of pro‐inflammatory mediators. Therefore, FGF2 contributes critically to disease amplification and chronicity [228].

Atherosclerosis is a chronic inflammatory vascular disease driven by the subintimal accumulation of lipids and inflammatory cells, a process that gives rise to atherosclerotic plaques, which can subsequently precipitate vascular stenosis, plaque rupture, and thrombosis [233]. Studies have shown that significantly elevated expression of FGF2 within atherosclerotic plaques is mainly produced by macrophages and vascular smooth muscle cells (VSMCs) residing in the lesions [175]. Upon binding to FGFR1 on VSMCs, FGF2 stimulates their proliferation and migratory activity while simultaneously activating the downstream RAS–MAPK/ERK cascade, contributing to intimal hyperplasia and atherosclerotic plaque progression [234, 235]. Additionally, FGF2 can bind to FGFR on endothelial cells to induce intraplaque neovascularization. However, when acting alone, the neo‐vessels induced by FGF2 are structurally fragile and exhibit insufficient pericyte coverage, rendering them prone to rupture and hemorrhage, which, in turn, increases plaque instability, predisposes to plaque rupture, and promotes thrombosis [176, 236]. Beyond its effects on VSMCs and endothelial cells, FGF2 also promotes macrophage chemotaxis and survival, activates NADPH oxidase to elicit oxidative stress, and amplifies local inflammatory responses [237, 238]. Collectively, these actions position FGF2 signaling as a critical driver of both plaque progression and vulnerability.

Cardiovascular Diseases

Hypertension is a clinical syndrome characterized by persistent elevation of systemic arterial pressure, with its pathophysiology primarily involving an imbalance between vasoconstriction and vasodilation, vascular remodeling, and endothelial dysfunction. It constitutes a major risk factor for cardiovascular and cerebrovascular events [239].

Under pathological conditions, the continuous aberrant expression of FGF2 in local blood vessels promotes VSMC proliferation and migration. Specifically, FGF2 binds to FGFR1 on VSMCs and activates downstream signaling cascades, including the RAS–MAPK/ERK pathway, which upregulates expression of proteins implicated in cell migration. This process contributes to vascular wall remodeling and thickening, indirectly affecting blood pressure regulation [180]. Additionally, abnormally elevated FGF23 in patients with chronic kidney disease (CKD) exerts direct cardiovascular toxicity [177]. High concentrations of FGF23 induce pathological cardiomyocyte hypertrophy by directly activating FGFR4 on cardiomyocytes through a Klotho‐independent mechanism. This signaling involves activation of PLCγ and the downstream calcineurin‐nuclear factor of NFAT pathway. Studies show that FGF23‐induced cardiomyocyte hypertrophy occurs even in the absence of Klotho. This mechanism represents a critical pathological basis for heart failure and cardiovascular death in patients with CKD [178, 240].

Cardiomyocyte hypertrophy represents an adaptive response of the heart to excessive pressure or volume load, but long‐term pathological hypertrophy may progress to heart failure, a condition characterized by a decline in cardiac pumping function that fails to meet the body's metabolic demands [241]. In addition to the direct pro‐hypertrophic effect of FGF23 mentioned above, local FGF/FGFR signaling in the heart is also involved. In a pressure overload‐induced model of cardiomyocyte hypertrophy, cardiac FGF2 expression is upregulated [242]. Paracrine FGF2 released by cardiac fibroblasts binds to FGFR1 on cardiomyocytes and activates MAPK signaling pathway, which drives cardiomyocyte hypertrophy. At the same time, FGF2 activates FGFR1 on cardiac fibroblasts. This receptor–ligand interaction does not merely drive fibroblast proliferation but also promotes their transformation into myofibroblasts and potentiates the production of TGF‐β and collagen. These changes collectively set the stage for myocardial interstitial fibrosis [243, 244]. In contrast to FGF2, FGF21 exerts cardioprotective effects. Under conditions of cardiac stress, FGF21 production is increased [85]. By binding to the FGFR1/β‐Klotho complex, FGF21 activates the PI3K–AKT, AMPK‐SIRT1‐PGC‐1α, and Nrf2 signaling pathways, exerting anti‐apoptotic, anti‐hypertrophic, and metabolic‐improvement effects on cardiomyocytes, while also reducing oxidative stress [85].

Tissue Fibrotic Diseases

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease in which aberrant scarring of the lung parenchyma drives a progressive deterioration of pulmonary function, culminating in hypoxemia and respiratory failure [245]. Studies have demonstrated that FGF/FGFR signaling plays a dual role in IPF. For instance, FGF2 is upregulated in the lung tissue of patients with IPF, where it promotes the proliferation and migration of lung fibroblasts and induces their differentiation into myofibroblasts upon binding to FGFR. Additionally, FGF2 signaling enhances the sensitivity of the TGF‐β pathway, synergistically facilitating the formation and expansion of fibrotic lesions [246, 247]. In contrast, FGF1 and FGF10 exhibit anti‐fibrotic potential. FGF1, for example, suppresses TGF‐β/Smad signaling, with a consequent reduction in myofibroblast differentiation and collagen deposition [248]. Besides, FGF10 primarily impedes fibrosis progression by maintaining the homeostasis and regenerative capacity of alveolar Type II epithelial cells [106].

Renal fibrosis represents the outcome of almost all CKDs progressing to end‐stage renal failure and is histopathologically characterized by the accumulation of activated myofibroblasts in the renal interstitium and excessive deposition of ECM collagen [249]. In the context of renal fibrosis caused by conditions such as diabetic nephropathy and chronic glomerulonephritis, injury to renal tubular epithelial cells leads to increased local FGF2 expression. Upon engagement with FGFR1, FGF2 drives the transformation of renal interstitial fibroblasts/pericytes into myofibroblasts. These activated cells then overproduce ECM components, including collagen, with consequent aggravation of interstitial fibrosis and deterioration of renal function [250]. In contrast, FGF21 has shown renoprotective effects in various animal models of CKD. In detail, FGF21 attenuates glomerulosclerosis and tubulointerstitial fibrosis by inhibiting NF‐κB/NLRP3 inflammasome activation, reducing macrophage infiltration, and decreasing the production of pro‐fibrotic factors, including TGF‐β1 and connective tissue growth factor (CTGF) [251]. Additionally, FGF1 also alleviates diabetic nephropathy damage through its anti‐inflammatory and antioxidant properties [252]. Building upon these findings, researchers have developed an FGF1 variant (FGF1ΔHBS), which upregulates PPARγ expression, enhances the interaction between PPARγ and SMAD3, and inhibits SMAD3 nuclear translocation in CKD mouse models [89]. This FGF1 variant further suppresses TGF‐β1/Smad3‐driven EMT, diminishing podocyte depletion and renal fibrosis [91].

Cancer

Cancer is a type of clonal neoplasm driven by abnormal genetic or epigenetic alterations in cells and represents the second leading cause of death worldwide [253]. Aberrant activation of FGF/FGFR signaling has been observed in a variety of malignant tumors, mainly driven by the dysregulated expression of FGF/FGFR, activating mutations of FGFR, and aberrant KLB receptors (Table 1). Aberrant activation of FGF/FGFR signaling constitutes a crucial oncogenic mechanism across multiple types of cancer, influencing tumor initiation, progression, and therapeutic response.

Aberration type | Involved FGF/FGFR members | Effects | Signaling pathway | Tumors | References
Ligand/receptor overexpression | FGF2 | Invasion, migration, angiogenesis | MAPK, PI3K/AKT, PLCγ | NSCLC, CRC | [64, 254]
FGF4 | Proliferation, survival, invasion | STAT3, MAPK, PI3K/AKT | TNBC | [195]
FGF8 | Proliferation, invasion, migration, angiogenesis | MAPK, PI3K–AKT, YAP1, PLCγ, JAK–STAT | PCa, BC, CRC, OSCC, HCC, ARMS | [255, 256, 257, 258, 259, 260]
FGF19 | Proliferation, anti‐apoptosis, metabolic reprogramming | RAS–MAPK, PI3K/AKT, GSK3β/Nrf2, SOCE/NFATc2, PLCγ, JAK–STAT | HCC | [72, 261, 262, 263]
FGF3 | Proliferation, survival | STAT3, PI3K/AKT, PLCγ | BC | [264]
FGFR1 | Proliferation, survival, invasion, angiogenesis | MAPK, PI3K/AKT, STAT3, PLCγ | LSCC, BC, OSCC, OC, GBM | [265, 266, 267, 268, 269]
FGFR2 | Proliferation, survival, invasion, migration | PI3K–AKT, MAPK, STAT3, PLCγ, JAK–STAT | GC, TNBC, EC, OC | [270, 271, 272, 273, 274, 275, 276]
FGFR3 | Proliferation, survival, anti‐apoptosis | STAT1, STAT3, PI3K/AKT, RAS/MAPK, PLCγ | Bladder cancer (non‐muscle‐invasive urothelial carcinoma, NMIUC), multiple myeloma with t(4;14) translocation | [277, 278]
FGFR4 | Proliferation, invasion, migration, immune evasion | STAT3, MAPK, PLCγ, JAK/STAT | HCC, GC, OC, NPC, CRC, ARMS | [279, 280, 281, 282, 283]
Gene amplification | FGF19 | Proliferation, survival, metabolic reprogramming | RAS/MAPK, PI3K/AKT, PLCγ, JAK/STAT | BC, LC, CRC, NPC, HNSCC | [284, 285, 286, 287, 288]
FGFR1 | Proliferation, survival, invasion | MAPK, PI3K/AKT, STAT3 | LSCC, BC, OSCC, OC, GBM | [265, 266, 267, 268, 269]
FGFR2 | Proliferation, survival | PI3K/AKT, MAPK | GC | [270, 271]
Gene mutation | FGFR1–TACC1 | Proliferation, invasion, survival | MAPK, PI3K/AKT, PLCγ, JAK/STAT | BC, NSCLC | [206]
FGFR3 (S249C/Y375C/R248C) | Tumor initiation, proliferation | RAS/MAPK, STAT3 | BC, CC (S249C) | [289, 290, 291]
FGFR3 (K650E) | Proliferation, survival | STAT1, PI3K/AKT | MM | [292]
FGFR2 (S252W/P253R) | Proliferation, survival | PI3K/AKT, MAPK | EC | [275, 293]
FGFR1 (V561M) | Proliferation, survival | MAPK, PI3K/AKT | LSCC | [294]
FGFR1 (K656E) | Tumor initiation, proliferation | PI3K/AKT/mTOR, RAS/MAPK | Glioneuronal tumor | [295]
FGFR4 (N535K/V550E) | Proliferation, invasion, migration | STAT3, PI3K/mTOR | ARMS | [283, 296]
FGFR4 (Y367C) | Proliferation | MAPK | BC | [296]
FGFR4 Gly388Arg (G388R, SNP) | Proliferation, invasion, migration | PI3K/AKT, MAPK, PLCγ | BC, PCa | [297, 298]
FGFR2‐BICC1/CCDC6/AHCYL1/TACC3 | Metastasis, invasion, survival | MAPK, PI3K/AKT, STAT | ICC | [299, 300, 301]
FGFR1 (N546K) | Tumor initiation, proliferation | MAPK | GBM | [302]
Gene fusion | FGFR1–TACC1 | Proliferation, invasion, survival | MAPK, PI3K/AKT, PLCγ, JAK/STAT | BC, NSCLC | [206]
FGFR3–TACC3 | Mitochondrial metabolic reprogramming, proliferation | MAPK, PI3K/AKT, PLCγ, STAT | LUSC, HNSCC, NPC | [303, 304, 305, 306, 307]
Aberrant Klotho co‐receptor | KLB overexpression | Proliferation, metastasis, metabolic reprogramming | PI3K/AKT/mTOR | HCC | [308]
KLB downregulation | Tumor initiation, immune evasion | — | EC, PCa, UDC | [263, 309, 310]

Aberrantly high expression of FGF dominantly drives tumor progression through autocrine and paracrine mechanisms [71]. FGF2, a key regulator of angiogenesis and EMT, exhibits high expression levels that are closely associated with poor prognoses of various solid tumors. For instance, in non‐small cell lung cancer (NSCLC), FGF2 overexpression engages FGFR1/2, with consequent activation of the downstream RAS–RAF–MEK–ERK signaling cascade. This signaling axis stimulates vascular endothelial cell proliferation and concurrently potentiates tumor cell invasion and metastasis [64]. Overexpression of FGF8 plays a significant oncogenic role in multiple types of cancer, including oral squamous cell carcinoma (OSCC) [257], HCC [258], alveolar rhabdomyosarcoma (ARMS) [259], breast cancer [260], prostate cancer [255], and colorectal cancer (CRC) [256]. For example, in prostate cancer, FGF8 activates the MAPK and PI3K–AKT pathways via FGFR1/2, thus propeling malignant cell progression [255]. Elevated FGF8 expression, in addition, drives CRC cell invasion and metastasis through EMT induction and activation of associated signaling cascades [256]. FGF19, a member of the endocrine FGF family, is encoded by a gene located at chromosomal region 11q13.3, which is frequently amplified in multiple cancers. This amplification leads to the overexpression of FGF19 protein and serves as a key driver of tumorigenesis [311]. Within HCC, FGF19 overexpression engages the FGFR4/β‐Klotho complex and activates the downstream RAS–MAPK and PI3K–AKT–mTOR pathways, with the consequence of driving hepatocyte malignant proliferation and suppressing apoptotic cell death [298, 312]. Additionally, FGF19 enhances the antioxidant defense and ER stress tolerance in HCC cells by activating the GSK3β/Nrf2 pathway [261]. And through the FGFR4/SOCE/NFATc2 signaling pathway, FGF19 promotes the self‐renewal of liver cancer stem cells (CSCs) [262]. Beyond HCC, FGF19 amplification and overexpression have been documented in a range of additional malignancies, including breast cancer [284], lung cancer [285], CRC [286], NPC [287], and head and neck squamous cell carcinoma (HNSCC) [288]. Elevated expression of additional FGF ligands, including FGF3, FGF4, and FGF9, has likewise been reported in breast cancer, gastric cancer, and other cancer types. For example, FGF3 overexpression promotes proliferation and EMT by binding to FGFR1 and activating the STAT3 pathway in breast cancer cells [264]. In TNBC, FGF4 overexpression drives TAMs toward M2 phenotype through activation of IL6/STAT3 signal axis, fostering immunosuppressive microenvironment that favors tumor progression and immune evasion [195].

Overexpression of FGFR receptors also constitutes a major cause of aberrant activation of FGF/FGFR signaling. FGFR1 amplification has been observed in multiple malignancies, including OSCC [267], ovarian cancer [268], glioblastoma [269], lung squamous cell carcinoma (LSCC), and breast cancer. For instance, in LSCC, FGFR1 amplification gives rise to protein overexpression and drives malignant progression via an FGF2–FGFR1 autocrine loop. This autocrine circuit sustains constitutive activation of downstream proliferative and survival signals [265]. Moreover, FGFR1 amplification occurs predominantly in hormone receptor‐positive subtypes of breast cancer and is associated with resistance to endocrine therapy [266]. FGFR2 gene amplification in gastric cancer results in elevated FGFR2 protein expression, a finding that correlates closely with unfavorable prognosis and lymph node metastasis [270, 271]. Among the various FGFR2 isoforms, FGFR2b is specifically overexpressed in gastric and gastroesophageal junction adenocarcinoma, where it promotes tumor cell proliferation and survival by activating the PI3K–AKT and MAPK signaling pathways [272, 273]. In breast cancer, FGFR2 overexpression has likewise been observed in certain TNBC subtypes, where it suppresses BRCA1 expression via activation of the STAT3 signaling pathway. This action drives TNBC tumorigenesis and fuels malignant progression [274, 313]. In CRC, FGFR2 overexpression can upregulate plasminogen activator inhibitor‐1 (PAI‐1) through activation of JAK2/STAT3 signaling axis. This upregulation drives TAM polarization toward the M2 phenotype, with the effect of establishing an immunosuppressive TME [254]. In addition, FGFR2 overexpression has been documented in various gynecological malignancies, including endometrial cancer (EC) [275] and ovarian cancer [276]. High expression of FGFR3 is relatively common in bladder cancer, particularly in non‐muscle‐invasive urothelial carcinoma. In certain cases, FGFR3 overexpression promotes tumor cell survival and proliferation via activating the STAT1 and STAT3 pathways [277, 278]. Moreover, FGFR3 overexpression is also observed in multiple myeloma, especially in cases harboring the t(4;14) translocation [277]. In addition, overexpression of FGFR4 plays an oncogenic role in various solid tumors. Within HCC, FGFR4 overexpression is associated with tumor invasiveness and poor prognosis, and binding of FGF19 to FGFR4 activates the STAT3 and MAPK pathways, which propels tumor progression [279]. In ovarian cancer, elevated FGFR4 expression is associated with advanced‐stage high‐grade carcinoma. Through MEK–ERK–RSK pathway activation, FGFR4 upregulates the anti‐apoptotic protein Bcl‐xL, thus conferring resistance to paclitaxel. Furthermore, stabilization of FGFR4 protein by SORL1 promotes carboplatin resistance, and targeting FGFR4 has been shown to enhance chemosensitivity [279, 281]. By activating the Wnt/β‐catenin pathway, FGFR4 overexpression facilitates EMT and invasion in CRC [282]. Besides, highly expressed FGFR4 has been observed in NPC tissues and cell lines and correlated with clinical stages and prognosis in NPC patients. In vitro experiments, FGFR4 induces cell proliferation and migration by regulating EMT markers [314]. Additionally, high FGFR4 expression is closely associated with advanced‐stage and poor survival in patients with rhabdomyosarcoma (RMS), and FGFR4‐activating mutations promote metastasis in mouse model [283].

Activating mutations within the FGFR family, including point mutations and gene fusions, represent key oncogenic drivers across various tumor types [299]. For instance, activating mutations in FGFR3 (e.g., S249C, Y375C, R248C) are most frequently observed in bladder cancer, and these alterations induce constitutive FGFR3 dimerization, with subsequent activation of the RAS–MAPK and STAT3 axes that drives tumorigenesis. In addition, FGFR3 establishes a positive feedback loop with MYC, conferring an oncogenic dependence [290, 315]. FGFR3 mutation, including S249C, is detected in cervical cancer [291], whereas the K650E alteration has been identified in multiple myeloma [292]. Additionally, point mutations in FGFR2 (e.g., S252W, P253R) are highly enriched in EC [275, 293, 316]. FGFR1 point mutations (V561M) are found in LSCC [294], and FGFR1 (K656E) mutations are mainly observed in glioblastoma [295]. Besides, FGFR4 mutations (e.g., N535K, V550E) are common in RMS [283, 296], and FGFR4 (Y367C) mutation is mainly found in the breast cancer cell line MDA‐MB‐453 [296]. Furthermore, the common FGFR4 Gly388Arg (G388R) polymorphism (SNP) is associated with poor prognosis in multiple types of cancer, including breast cancer [297] and prostate cancer [298].

FGFR gene fusions constitute another important class of oncogenic events. FGFR2 gene fusions are characteristic driver alterations in intrahepatic cholangiocarcinoma, with common fusion partners, including FGFR2–BICC1, FGFR2–CCDC6, FGFR2–AHCYL1, and FGFR2–TACC3. These fusion proteins drive ligand‐independent and constitutive activation of the FGFR2 kinase domain. The resultant signaling, through activation of the MAPK, PI3K–AKT, and STAT pathways, promotes malignant transformation of cholangiocytes [300, 301, 317]. FGFR3–TACC3 gene fusions are most prevalent in LUSC [303], IDH‐wild‐type glioma [304], HNSCC [305], and NPC [306]. Notably, this fusion protein can also aberrantly localize to mitochondria, where it induces metabolic reprogramming in tumor cells [307]. Other fusions, such as FGFR1–TACC1 fusions, have been reported in glioblastoma (including GBM) and specific mesenchymal tissue tumors, including spinal cord glioma and uterine sarcoma [318, 319].

The Klotho protein family exhibits aberrant expression that modulates FGF/FGFR signaling and systemic homeostasis, thereby contributing to the pathogenesis and progression of various tumors [320]. β‐Klotho (KLB) is an essential co‐factor for FGF19 and FGF21 signaling and is predominantly expressed in the liver [321]. KLB is implicated in tumorigenesis, with its expression levels and those of its mutants varying across different cancer types. Elevated KLB expression is significantly associated with poor prognosis of HCC patients [308]. Mechanistically, upregulated KLB promotes the proliferation and migration of HCC cells and enhances FGFR4‐mediated downstream signaling by activating the PI3K/Akt/mTOR pathway. Consequently, silencing of KLB exerts an anti‐proliferative effect in HCC, suggesting that KLB may represent a novel therapeutic target for HCC [308]. However, conflicting evidence also suggests that KLB‐FGFR4 co‐expression induces apoptosis via modulation of the Akt/mTOR pathway, with the consequence of suppressing HCC development [322]. The KLB Arg728 allele mutation compromises KLB protein stability and impairs its interaction with FGF19. These effects attenuate downstream signaling and upregulate CYP7A1 expression, collectively predisposing to nonalcoholic fatty liver disease (NAFLD) and cancer [323, 324]. In NSCLC, KLB overexpression alters the cell cycle and inhibits the ERK1/2, AKT, and STAT3 signaling pathways, underling its potential antitumor activity. Accordingly, the serum KLB level may serve as a clinically applicable biomarker for NSCLC diagnosis [325]. In addition, KLB is downregulated in EC [263], prostate cancer [309], and invasive ductal carcinoma of the breast [310], and its overexpression inhibits tumorigenesis. Collectively, these findings underscore that the expression levels and functional mechanisms of KLB vary markedly across different tumors, highlighting its non‐negligible role in oncogenesis.

Attenuated FGF/FGFR Signaling

Conversely, attenuated FGF/FGFR signaling, caused by reduced FGF expression, loss of FGFR function, resistance to signaling pathways, or failure of endogenous protective mechanisms, can also contribute to the pathogenesis of various diseases, including metabolic disorders, inflammatory diseases, neurological diseases, and developmental abnormalities.

Metabolic Diseases

Metabolic syndrome is a clustering of metabolic risk factors, including obesity, hypertension, hyperglycemia, and dyslipidemia, and is often accompanied by complications such as Type 2 diabetes and NAFLD/NASH [326]. FGF21 is an endocrine hormone primarily secreted by the liver. Through engagement with the FGFR1c/β‐Klotho complex, FGF21 activates the downstream AMPK signaling cascade. This activation upregulates PPARα and PGC‐1α, with consequent stimulation of FAO and ketogenesis. Moreover, FGF21 also enhances energy expenditure and facilitates GLUT4 translocation, displaying the capability of reducing plasma glucose and triglycerides, as well as improving insulin sensitivity [327]. However, in patients with obesity and metabolic syndrome, although circulating FGF21 levels are significantly elevated in a compensatory manner, its metabolic regulatory function is impaired, a phenomenon known as FGF21 resistance [328]. Exogenous administration of recombinant FGF21 or its long‐acting analogs has been demonstrated to elicit significant improvements in metabolic parameters, as evidenced by both preclinical animal studies and clinical trials [17, 329]. FGF21 also exhibits antioxidant properties. Mechanistically, it activates the Nrf2 signaling axis, potentiates antioxidant enzyme activity, and attenuates oxidative stress‐induced cellular damage [330]. Collectively, these findings establish FGF21 not only as a biomarker for metabolic syndrome and related diseases, but also as an important therapeutic target.

FGF19 serves as a key signaling molecule in the gut–liver axis [331]. Following meal, elevated intestinal BA levels activate the farnesoid X receptor (FXR), which induces the secretion of FGF19 from intestinal epithelial cells. Upon reaching the liver, FGF19 engages the FGFR4/β‐Klotho receptor complex on hepatocytes and subsequently activates downstream signaling pathways and represses CYP7A1 expression. This negative feedback mechanism prevents excessive BA synthesis and hepatotoxicity, preserving BA metabolic homeostasis [332]. However, once FGF19 signaling is disrupted, CYP7A1 becomes overexpressed, leading to BA accumulation in the liver. These accumulated BAs trigger mitochondrial dysfunction and ROS overproduction, which, in turn, inflict damage on hepatocytes [333, 334]. Moreover, chronic BA accumulation further triggers liver inflammation, activation of HSCs, and collagen deposition, ultimately progressing to liver fibrosis, cirrhosis, and even HCC [332, 335]. Insufficient FGF19 signaling, beyond its effects on BA synthesis, may compromise biliary epithelial cell integrity, further worsening BA accumulation [336]. Under conditions of BA accumulation, FGF19 upregulates the expression of multidrug resistance‐associated proteins (MRP)‐3/4 via activation of the ERK pathway, thereby mitigating hepatocyte damage [337]. The therapeutic promise of these insights has been borne out in both animal models and human trials, where FGF19 analogs have shown efficacy in cholestatic conditions like primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), as well as metabolic disorders including NASH. The underlying mechanism centers on reduced BA production and attenuated liver fibrosis [332].

Inflammatory Diseases

Sepsis, defined as life‐threatening organ dysfunction caused by a dysregulated host response to infection, and systemic inflammatory response syndrome (SIRS), an excessive systemic inflammatory response triggered by either infectious or non‐infectious stimuli, represent two critical clinical conditions [338]. In patients with sepsis and experimental animal models, plasma FGF21 levels rise sharply during the early stage of the disease, reflecting an adaptive stress response [339]. Studies have demonstrated that exogenous administration of FGF21 significantly improves survival rates and alleviates multiple organ dysfunction in septic mice [340]. Mechanistically, by restoring autophagic flux in macrophages and promoting p62‐mediated autophagic degradation of hypoxia‐inducible factor 1 alpha (HIF‐1α), FGF21 curbs pro‐inflammatory macrophage activation and dampens the inflammatory storm [341]. Similar to FGF21, FGF1 also exhibits anti‐inflammatory and organ‐protective properties. In septic mice, FGF1 suppresses inflammatory cytokine release through inhibition of IL‐6/STAT3 pathway [342]. Beyond its direct anti‐inflammatory action, FGF1 preserves endothelial barrier integrity, suppresses apoptosis, and stimulates angiogenesis, ultimately mitigating liver injury and coagulation dysfunction [343]. Under conditions of excessive inflammation such as sepsis and IBD, endogenous protective FGF/FGFR signaling may be insufficient to counteract the intense inflammatory response, suggesting that exogenous supplementation with FGF21 or FGF1 holds therapeutic potential.

Nervous System Diseases

Epilepsy is a chronic neurological disorder characterized by recurrent and transient central nervous system dysfunctions resulting from highly synchronized abnormal neuronal discharges in the brain [344]. FGF/FGFR signaling plays a regulatory role in both epileptogenesis and synaptic plasticity. FGF22 and FGF7 exert opposing effects on synapse formation: FGF22 tends to promote excitatory synapse formation, whereas FGF7 tends to facilitate the formation of inhibitory synapses [155]. In Fgf22 knockout mice, the aggregation of excitatory synaptic vesicles in the CA3 region of the hippocampus is reduced, and the miniature excitatory postsynaptic currents (mEPSCs) are diminished, leading to relatively enhanced synaptic inhibition. Consequently, these mice exhibit reduced susceptibility to electrically induced epileptic seizures [345], suggesting that the absence or downregulation of FGF22 signaling exerts an antiepileptic effect by reducing excitatory synapses. Conversely, insufficient or absent FGF7 signaling leads to reduced levels of the VGAT protein at the presynaptic terminals of GABAergic neurons projecting to the CA3 region, a decrease in the frequency of mIPSCs, and a shift in the excitation/inhibition (E/I) balance toward excitability, ultimately increasing susceptibility to seizures [155, 345].

Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the progressive loss and dysfunction of specific neuronal populations, accompanied by pathological processes such as protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation [346]. The FGF family has attracted considerable attention for its neurotrophic, neuroprotective, neurogenic, and anti‐inflammatory properties in neurodegenerative disorders [347]. In an in vitro model of embryonic midbrain dopaminergic neurons, FGF2 exerts significant trophic and protective effects on dopaminergic neurons. This action is achieved through stimulation of astrocytes and synergistic cooperation with factors such as TGF‐β [88]. Additionally, in an animal model of Alzheimer's disease, FGF21 enhances antioxidant defense by activating the Nrf2 pathway, thereby reducing oxidative damage to amyloid‐beta (Aβ) and tau proteins. Simultaneously, FGF21 also inhibits the NF‐κB pathway, leading to decreased release of pro‐inflammatory factors, reduced levels of Aβ and phosphorylated tau, and improved cognitive function [348]. Nevertheless, most of these studies remain at the preclinical stage, and their translation into clinical application faces numerous challenges.

Sensory ataxia refers to a condition marked by impaired proprioception that gives rise to pronounced ataxia when visual input is compromised, for instance, with eyes closed. Genetic factors are among the primary etiologies of this disease [349, 350, 351]. Studies have demonstrated that in mice lacking the FGF14 gene, voltage‐gated sodium channels in Purkinje neurons and granule cells exhibit dysfunction, and the animals display significant ataxia and paroxysmal dyskinesia [352]. Loss of FGF14 leads to reduced Nav channel expression and aberrant channel kinetics, which subsequently impairs the initiation and propagation of action potentials [353, 354]. In humans, mutations in FGF14 are associated with autosomal dominant cerebellar ataxia. These mutations prevent the FGF14 protein from normally binding to the Nav channel alpha subunit [355]. Furthermore, mutant FGF14 interferes with wild‐type FGF14 function through a dominant‐negative mechanism, giving rise to clinical features including progressive ataxia, paroxysmal dyskinesia, and cognitive decline [356].

Chronic Wound Healing Disorder

Chronic wounds are defined as those that fail to restore normal anatomical structure and functional integrity, frequently marked by a healing process that stalls in the inflammatory phase, driven by factors such as persistent inflammation, impaired angiogenesis, or cellular senescence [357]. The FGF family plays a crucial role in orchestrating the wound healing process. During the early stages of normal wound healing, FGF2, primarily released by platelets, macrophages, and injured endothelial cells, significantly promotes the proliferation and migration of fibroblasts, endothelial cells, and keratinocytes [75]. Moreover, by inducing EMT, FGF2 enables keratinocytes to acquire migratory capacity, which is essential for granulation tissue formation and epithelial regeneration [76, 358, 359]. Dermal fibroblasts secrete FGF7 as a paracrine factor, which drives keratinocyte proliferation via its cognate receptor FGFR2IIIb. During wound re‐epithelialization, FGF7 levels are remarkably upregulated, subsequently enhancing cell migration by increasing the activity of urokinase‐type plasminogen activator (uPA) and reducing apoptosis induced by ROS. Together, these effects of FGF7 facilitate the completion of re‐epithelialization process [96, 97]. However, in chronic wounds, multiple factors collectively contribute to FGF/FGFR signaling dysfunction. Markedly elevated protease activity leads to excessive degradation of growth factors such as FGF2 [360]. A hyperglycemic microenvironment also reduces cellular responsiveness to growth factors [361]. Moreover, a persistent inflammatory milieu inhibits cell proliferation and matrix remodeling [362, 363], leading to pro‐repair signaling pathways, particularly those mediated by FGF2 and FGF7, that are impaired. As a result, wound healing becomes stalled in the inflammatory phase, granulation tissue formation is compromised, and re‐epithelialization remains incomplete [364]. Consequently, local administration of recombinant FGF2 or FGF‐based topical therapies represents an effective strategy for managing chronic wounds.

Excessive Bone Growth

Gain‐of‐function mutations in FGFR3 cause a spectrum of skeletal dysplasias characterized by disproportionate short stature, including ACH and thanatophoric dysplasia (TD). Conversely, loss‐of‐function mutations in FGFR3 underlie CATSHL syndrome, defined by camptodactyly, tall stature, scoliosis, and sensorineural hearing loss, a condition marked by excessive bone growth [365, 366, 367]. To date, several families with CATSHL syndrome have been reported, carrying either heterozygous or homozygous pathogenic variants in FGFR3, including p.Arg621His, p.Gly369Cys, and p.Thr546Lys. All identified variants reside within the RTK domain and lead to loss of FGFR3 signaling function. At the mechanistic level, inactivating FGFR3 variants attenuate the activities of STAT and MAPK pathways. Consequently, expression of key cell cycle inhibitors, including p16, p18, and p19, is downregulated, leading to enhanced chondrocyte proliferation. Consistent with this mechanism, Fgfr3 knockout mice display markedly elongated spines and long bones, accompanied by an expansion of the hypertrophic zone and delayed exit from the proliferative zone in the growth plate [368].

In conclusion, dysregulated FGF/FGFR signaling, whether due to pathological hyperactivation or loss‐of‐function, disrupts systemic homeostasis and contributes to the pathogenesis of diverse diseases. This bidirectional nature of FGF/FGFR signaling underscores the functional pleiotropy and context‐dependent regulatory precision of this signaling network.