Functions of FGF/FGFR Signaling

The Role of FGF/FGFR Signaling in Regulating Cellular Functions

By transducing extracellular cues into precisely coordinated intracellular responses via sequential phosphorylation cascades and context‐dependent transcriptional regulation, the FGF/FGFR signaling plays a pivotal role in the regulation of fundamental cellular processes, including cell proliferation, survival, migration, differentiation, polarization, and self‐renewal of stem cells (Figure 3).

FIGURE 3: FGF/FGFR signaling regulates multiple cellular biological processes. Different FGF ligands exert extensive regulation on cellular activities by activating specific FGFR downstream signaling cascades. FGF9 activates the MAPK/ERK and PI3K/AKT cascades to accelerate cell cycle progression and promote cell proliferation. FGF21 transmits FGFR‐mediated signaling to suppress various cell death programs, including apoptosis, ferroptosis, and pyroptosis, so as to support cell survival. FGF2 induces EMT through the MAPK/ERK and PI3K/AKT pathways, thereby facilitating cell migration. FGF6 modulates the Ca2+/calcineurin/NFAT signaling axis to mediate the differentiation of myoblasts into mature myocytes. FGF10 maintains the stemness and self‐renewal of alveolar stem cells via FGFR2‐dependent signaling. FGF19 regulates mitochondrial oxidative phosphorylation (OXPHOS) through the FGFR4/mTOR/S6K/PGC‐1α pathway, thereby driving M2 macrophage polarization. Created with Biorender.com. EMT, epithelial–mesenchymal transition; MΦ, macrophage; MAPK, mitogen‐activated protein kinase; PI3K, phosphatidylinositol 3‐kinase; RAS, rat sarcoma.

Cell Proliferation

Cell proliferation, a fundamental biological process that increases the number of cells in an organism and is achieved through the orderly progression of the cell cycle, is crucial for the growth, development, tissue repair, and regeneration of the organism [68]. FGF/FGFR signaling serves as a pivotal regulator of cell cycle processes and cell proliferation. Central to this effect is the classical RAS–MAPK pathway, wherein activated ERK1/2 phosphorylates diverse transcription factors and cell cycle regulators to facilitate the G1‐to‐S phase transition [50, 69, 70]. However, the impact of FGF/FGFR signaling on cell proliferation is bidirectional, as it can either promote cell cycle progression or induce cell cycle arrest, depending on the specific cell type and physiological context. Multiple FGF/FGFR signalings drive cell cycle progression by activating distinct downstream pathways. In various cancer cells, activating mutations or fusions of FGFR lead to sustained activation of MAPK and PI3K–AKT pathways, thereby endowing tumor cells with unlimited proliferative capacity [71, 72, 73]. During tissue repair, FGF2 binds to FGFR1/2 receptors to activate the Ras–MAPK/ERK signaling pathway, which drives the proliferation and directed migration of fibroblasts, endothelial cells, and keratinocytes. This pleiotropic mitogenic effect significantly promotes wound healing and re‐epithelialization [74, 75, 76]. Similarly, in osteoblasts, FGF2 and FGF8 upregulate the transcription factor runt‐related transcription factor 2 (Runx2) through FGFR1 signaling. Then, Runx2 activates downstream targets such as Osterix, collectively promoting osteoblast proliferation and differentiation and contributing to osteogenesis [77, 78].

Conversely, FGFR3 plays a negative regulatory role in bone development. It exerts an inhibitory effect on bone development by initiating the STAT1 signaling cascade. Activation of the FGFR3‐STAT1 signaling pathway leads to upregulated p21 expression, which arrests chondrocytes at the G1 phase of the cell cycle, ultimately suppressing the process of endochondral ossification [79, 80, 81].

Cell Survival

Cell survival is a fundamental cellular process essential for tissue homeostasis, development, and stress adaptation. It is governed by tightly regulated molecular mechanisms, including anti‐apoptotic signaling, regulated necrosis, and cytoprotective autophagy [82].

FGF2 possesses cardioprotective functions. Studies have shown that FGF2 exerts cardioprotective effects by activating the MAPK and PI3K–AKT signaling pathways, inhibiting mitochondria‐ and death receptor‐mediated apoptosis, improving cardiac functional outcomes after ischemia‐reperfusion injury, and maintaining myocardial contractile function [83, 84]. FGF21 enhances cardiac tolerance by binding to the FGFR1/β‐Klotho receptor complex on cardiomyocytes, thereby activating downstream AMPK and PI3K–AKT signaling pathways. This activation subsequently upregulates mitochondrial uncoupling protein 3 (UCP3) and superoxide dismutase 2 (SOD2) expression, curtails reactive oxygen species (ROS) accumulation to attenuate oxidative stress, and suppresses caspase‐3 cleavage, collectively improving cardiomyocyte survival and metabolic adaptation under stress conditions [85]. In the nervous system, FGF2 promotes the development of midbrain dopaminergic neurons via FGFR3‐dependent activation of the MAPK/ERK signaling cascade. In contrast, FGF20 functions as a paracrine survival factor within the adult brain, engaging FGFR1c and activating the PI3K–AKT axis to mediate its effects [86, 87]. Thus, both FGF ligands promote dopaminergic neuron survival via spatially and temporally distinct signaling mechanisms. Consistent with these findings, in vitro studies using primary embryonic midbrain dopaminergic neuron cultures have demonstrated that FGF2 induces robust upregulation of transforming growth factor‐beta (TGF‐β), which, in turn, mediates potent neurotrophic and anti‐apoptotic effects [88]. In renal epithelial cells, FGF1 and its engineered heparin‐binding–deficient variant FGF1ΔHBS exert renoprotection through PI3K–AKT activation, with consequent suppression of oxidative injury and production of pro‐inflammatory cytokines [89].

Additionally, ferroptosis is a type of programmed cell death that is iron‐dependent and characterized by the accumulation of lipid peroxides [90]. The FGF/FGFR signaling plays a significant role in the regulation of ferroptosis. For instance, FGF12 protects cardiomyocytes from doxorubicin‐induced ferroptosis through activation of the FGFR1/AMPK/nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway, an effect that limits cardiac injury [91]. In addition, FGF2 alleviates ischemia‐reperfusion injury by activating the Krüppel‐like factor 2 (KLF2)‐Nrf2 signaling axis in the microvascular system, thereby inhibiting ferroptosis in microvascular endothelial cells and reducing microvascular dysfunction [92], further illustrating the context‐dependent anti‐ferroptotic role of FGF/FGFR signaling.

Besides, pyroptosis is a lytic and pro‐inflammatory form of programmed cell death mediated by the gasdermin family of proteins, playing a crucial role in infection immunity, sterile inflammation, and organ damage [93]. In acute kidney injury (AKI), FGF23 confers protection through induction of FGFR4‐dependent autophagy, an event that antagonizes gasdermin E (GSDME)‐mediated pyroptosis and preserves renal function [94]. Overall, FGF/FGFR signaling enhances cellular viability by suppressing multiple cell death pathways, such as apoptosis, ferroptosis, and pyroptosis.

Cell Migration

Cell migration refers to the process by which cells move directionally from their original location to a target location. This dynamic process plays a crucial role in diverse biological processes, including embryonic development, tissue repair, inflammatory responses, and tumor cell dissemination [95]. Accumulating evidence has demonstrated that the FGF/FGFR signaling is involved in regulating cell migration across multiple cell types. For instance, in keratinocytes, FGF2 drives wound‐edge cell migration and re‐epithelialization by upregulating epithelial–mesenchymal transition (EMT)‐related transcription factors, including Snai2, alongside TGF‐β pathway‐associated genes. Consequently, epithelial adhesion molecules are downregulated, mesenchymal markers upregulated, and β‐catenin translocates to nucleus, thereby promoting wound healing [76]. Additionally, FGF7 binds to keratinocyte‐specific receptor FGFR2IIIb, activating the MAPK/ERK and PI3K/AKT cascades and concurrently driving the proliferation and migration of keratinocytes and facilitating wound re‐epithelialization [96, 97]. Besides, in myoblasts, FGF2 and FGF6 significantly enhance chemotactic migration by synergistically promoting adhesion to the ECM and facilitating cytoskeletal reorganization [98]. Furthermore, FGF13 stabilizes the microtubule network in neurons through direct binding with microtubules, simultaneously exerting dual regulatory functions that promote polymerization and inhibit depolymerization, thereby driving neuronal polarization and migration [99].

Cell Differentiation

Cell differentiation refers to the process by which unspecialized cells acquire specific forms and functions during development, serving as the foundation of embryonic development, tissue formation, and organ function establishment [100]. This process involves changes in cell morphology, physiological characteristics, and other cellular features, enabling cells to perform distinct biological functions. During bone development, FGF9 binds to the FGFR3c and activates the MAPK/ERK signaling pathway, thereby modulating the differentiation of early hypertrophic chondrocytes [101]. Moreover, FGF6 triggers the Ca2+/calcineurin/nuclear factor of activated T cells (NFAT) cascade in myoblasts, a signaling axis that upregulates myogenic determinants, including MYOG, to commit cells to differentiation [102]. Meanwhile, FGF20 drives the differentiation of inner ear progenitors through FGFR1–MEKK4‐mediated upregulation of Sox2 and Atoh1, two transcription factors essential for sensory cell specification [103].

Self‐Renewal of Stem Cells

Self‐renewal is the ability of stem cells to maintain the characteristics of stem cells in at least one of their daughter cells during cell division, representing a key attribute that sustains the proliferative capacity of stem cell populations [104]. FGF/FGFR signaling promotes the self‐renewal potential of various adult stem cells by regulating multiple signaling pathways [105]. In nephron progenitor cells, FGF9 and FGF20 bind to FGFR1c and transduce signals through the Ras–MAPK/ERK cascade to elevate the expression of Six2, a transcription factor that maintains stemness. This regulation maintains the stemness characteristics of metanephric mesenchymal stem cells while promoting their differentiation into nephron lineages [106]. Additionally, FGF10 binds to the FGFR2b receptor to activate the PI3K/AKT and Ras–MAPK/ERK pathways, thus modulating the expression balance of Sox9 and Sox2 in alveolar epithelial progenitor cells [106]. This mechanism maintains the pool of distal progenitor cells and drives both the homeostasis and regeneration of alveolar epithelial cells after injury.

With age, aging is accompanied by a marked decline in FGF2 expression within hippocampal astrocytes, thereby leading to attenuation of FGFR1/MAPK/ERK signaling. Consequent to this signaling attenuation, neural stem cells undergo proliferative arrest and precocious differentiation, compromising their self‐renewal potential [107]. During the regeneration process following muscle injury, 11,12‐epoxyeicosatrienoic acid (11,12‐EET) amplifies FGF/FGFR signaling by enhancing the phase separation of FGF ligands on the membrane surface, a process that promotes the proliferation and differentiation of muscle stem cells (MuSCs) [108].

Cellular Polarization

Cellular polarization refers to the establishment of intracellular and functional asymmetry necessary for fulfilling specialized biological roles, representing a critical process in various physiological and pathological contexts [109]. Increasing evidence highlights that FGF/FGFR signaling orchestrates cell polarization in diverse conditions. Specifically, in the neuroectoderm, FGFR1 directly interacts with the core planar cell polarity (PCP) protein Vangl2 and phosphorylates its N‐terminal tyrosine residues. This mechanism is essential for the establishment of PCP and underpins critical morphogenetic events, including neural tube closure [110]. Recently, our team has found that FGF19/FGFR4 signaling drives macrophages toward M2 polarization via activation of the mTOR/ribosomal protein S6 kinase (S6K)/peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) pathway, which enhances the immunosuppressive activity of macrophages [111]. Similarly, FGF21 promotes the conversion of microglia from the pro‐inflammatory M1 phenotype to the anti‐inflammatory M2 phenotype via the SIRT1/NF‐κB pathway, exerting neuroprotective effects [112]. Collectively, these findings underscore the multifaceted roles of FGF/FGFR signaling in orchestrating polarization in development and immune regulation contexts.

The Role of FGF/FGFR Signaling in Regulating Physiological Functions

By precisely regulating a series of key cellular behaviors, such as cell proliferation, survival, migration, invasion, and differentiation, FGF/FGFR signaling exerts a multidimensional influence over the physiological functions of the organism. It not only orchestrates fundamental life processes, such as embryonic development, tissue repair, immune regulation, and aging, but also plays an integral role in maintaining systemic metabolic homeostasis [5, 113, 114] (Figure 4).

FIGURE 4: Effects of FGF/FGFR signaling on physiological functions in vivo. FGF/FGFR signaling is widely involved in various biological processes. (A) During embryonic development, FGF4 upregulates GATA4 expression to regulate hypoblast formation. (B) In tissue repair and regeneration, FGF2 at wound sites promotes the remodeling of regenerative epithelium. (C) Under starvation and cold stress, liver‐secreted FGF21 acts on adipose tissue to enhance glucose uptake and fatty acid oxidation, thereby maintaining systemic metabolic homeostasis. (D) During neural system development, FGF8 induces the differentiation of induced pluripotent stem cells into mature neurons. (E) In bone development, FGF2, FGF9, and FGF18 promote osteoblast maturation and bone formation. (F) FGF2 activates endothelial cells to mediate angiogenesis. (G) In the regulation of aging, FGF21 improves insulin sensitivity and reduces fat accumulation to alleviate aging‐related disorders. (H) In the tumor immune microenvironment, FGF4 secreted by TNBC cells induces M2 macrophage polarization by activating STAT3, leading to immunosuppression. Created with Biorender.com. iPSCs, induced pluripotent stem cells; MAPK, mitogen‐activated protein kinase; PI3K, phosphatidylinositol 3‐kinase; RAS, rat sarcoma; TNBC, triple‐negative breast cancer.

Embryonic Development

Embryonic development is a process by which a single fertilized egg transforms into a complex multicellular organism, relying on a series of precise and complex regulatory mechanisms [115]. During this process, FGF/FGFR signaling guides the morphogenesis and development of various organs through distinct spatiotemporal expression patterns. In limb development, FGF8, secreted by the apical ectodermal ridge (AER), and FGF10, derived from the mesenchyme, form a positive feedback loop through FGFR2b. FGF10 induces FGF8 expression in the AER, whereas FGF8 sustains FGF10 expression in the mesenchyme, thereby driving limb bud initiation, continuous outgrowth, and the formation of the proximodistal pattern [116, 117, 118]. FGFR1 promotes mesenchymal cell survival and proximodistal elongation in the early limb bud, thus driving limb initiation. In contrast, deficiency of FGFR1 leads to mesenchymal cell apoptosis, abnormal AER formation, and downregulation of Sonic hedgehog (Shh) expression, severely disrupting the limb initiation process [119, 120]. In respiratory system development, the FGF10–FGFR2b signal drives the expression of a cohort of development‐related genes through the β‐catenin/EP300 transcriptional complex. This mechanism maintains the stemness of distal epithelial progenitor cells and regulates cell adhesion and rearrangement, thereby driving the repeated branching morphogenesis of the bronchial tree [121, 122, 123].

Additionally, FGF9 and FGF18, derived from mesothelial and epithelial cells, respectively, cooperate to regulate lung parenchymal expansion and alveolarization through actions on distinct mesenchymal subregions. FGF9 participates in WNT/β‐catenin signaling to regulate smooth muscle differentiation, whereas FGF18 upregulates mesenchymal genes such as SOX9 via FGFR3 and contributes to epithelial branching [124, 125, 126, 127]. In kidney development, FGF10 secreted by the metanephric mesenchyme binds to FGFR2b at the tip of the ureteric bud, a receptor–ligand interaction that stimulates MAPK/ERK signaling to drive ureteric bud branching and elongation. In parallel, in response to signals from the ureteric bud tip, FGF9 and FGF20 secreted by the cap mesenchyme bind to FGFR1/FGFR2 within the mesenchyme, leading to MAPK/ERK‐mediated upregulation of Six2. This mechanism maintains the stemness of nephron progenitor cells and drives their differentiation toward the nephron lineage [128, 129, 130]. Concurrently, FGF8, originating from the mesoderm, inhibits BAX/BAK‐mediated mitochondrial apoptosis to sustain the survival of nephron progenitor cells. Working together with WNT4, FGF8 upregulates Lhx1 to initiate renal tubule differentiation, a step that propels the formation of nascent nephrons [130].

In addition, multiple FGF ligands, such as FGF3, FGF8, FGF10, and FGF20, are involved in distinct stages of inner ear development. At the onset of otic placode induction, endodermal FGF8 triggers FGF19 expression in the adjacent mesoderm. FGF19 then signals the neuroectoderm, where it upregulates WNT8c and FGF3, which together initiate otic placode formation [131]. At the otic vesicle stage, FGF3 and FGF10 bind to FGFR2b to maintain the survival of neural progenitor cells within the otic vesicle and regulate the formation and proliferation of epithelial patterns; these processes coordinate the morphogenesis of the cochlea and vestibule [132]. FGF20, under the regulation of notch signaling, promotes the differentiation of the prospective sensory epithelium into hair cells during sensory hair cell differentiation [103]. Meanwhile, FGF8 secreted by inner hair cells regulates the differentiation of local supporting cells into pillar cells [133]. In the developing nervous system, gradient signals composed of FGF8 and FGF17 regulate the proliferation and differentiation of the midline structures in the cerebellum, ultimately impact cerebellar architecture and function [134].

Tissue Repair and Regeneration

Tissue repair refers to the biological process by which the body restores the structural integrity and function of injured tissues through multiple ordered stages, such as blood coagulation, inflammation, and cell proliferation [135]. Unlike embryonic development, tissue repair requires the rapid mobilization of diverse cellular responses triggered by injury signals, and FGF/FGFR signaling is extensively involved in this injury response and repair process [136]. Following skin injury, FGF2 expression increases rapidly, leading to the activation of FGFR–MAPK signaling in endothelial cells and promoting angiogenesis. Simultaneously, FGF2 drives fibroblast proliferation and collagen deposition for granulation tissue formation, while also promoting keratinocyte migration and proliferation to expedite epithelial regeneration [74, 137]. Collectively, these actions accelerate wound healing. In contrast, although FGF7 regulates hair follicle development by binding to the FGFR2b receptor on keratinocytes, its function in skin wound repair can be partially compensated by FGF10, demonstrating a certain degree of functional substitutability [138].

During skeletal muscle regeneration, FGF6 activates the ERK1/2 signaling pathway via FGFR1 and FGFR4 to upregulate myogenin expression, which subsequently drives myoblast differentiation and promotes muscle repair [102]. Besides, FGF2 and FGF6 jointly activate the MAPK/ERK and PI3K/Akt pathways in muscle stem cells, synergistically promoting myoblast migration. The concurrent absence of both ligands leads to migration defects and hinders the muscle regeneration process [98]. In response to pressure overload, FGF2 secreted by cardiomyocytes activates downstream pathways, such as MAPK, to induce adaptive cardiac hypertrophy [139]. Furthermore, cardiac‐specific overexpression of FGF2 enhances the MAPK signaling cascade, thus alleviating myocardial damage evoked by ischemia‐reperfusion injury [83, 84].

In addition, FGF/FGFR signaling also plays a crucial role in liver regeneration, which refers to the capacity of the remaining liver tissue to restore its original structure and function after partial resection or injury [140]. During this process, FGF15/19 (FGF15 in mice, FGF19 in humans) secreted by the intestine acts on the liver via the portal circulation. Through binding with FGFR4/KLB complex, FGF15/19 signaling activates the MAPK/ERK and PI3K/AKT pathways, driving hepatocyte proliferation and tissue repair [141, 142]. In lung injury models, FGF2 mitigates injury by preserving the integrity of the alveolar epithelial barrier. Meanwhile, FGF10 exerts dual protective effects: It suppresses the NF‐κB pathway to produce anti‐inflammatory actions in the early stage and inhibits the TGF‐β/Smad pathway to mediate anti‐fibrotic effects in the late stage. Collectively, these coordinated actions alleviate bleomycin‐induced pulmonary fibrosis [143, 144].

Metabolic Homeostasis

Metabolic homeostasis refers to the body's ability to maintain relatively constant metabolic parameters through fine‐tuned regulation in response to changes in internal and external environments [145]. The maintenance of this balance requires the coordinated cooperation among different tissues and organs, in which endocrine FGFs serve as important signaling molecules that connect these organs. Especially, endocrine FGFs (FGF15/19, FGF21, and FGF23) form a unique systemic metabolic regulatory network. Acting as hormones, they travel through the bloodstream to distant target organs, where they maintain energy and material metabolic balance [146].

FGF21 is mainly synthesized in the liver. Under conditions of hunger or cold stress, the liver upregulates FGF21 expression via peroxisome proliferator activated receptor (PPAR)‐α. Upon reaching adipose tissue, FGF21 binds to the β‐Klotho/FGFR1c receptor complex to promote glucose uptake and lipolysis. At the same time, it enhances fatty acid oxidation (FAO) and ketogenesis in the liver, jointly maintaining the energy homeostasis [147, 148, 149, 150]. FGF19 is produced by ileal cells upon stimulation of BAs and enters the liver through the portal circulation. It then binds to the FGFR4/β‐Klotho complex on the hepatocytes, inhibiting the expression of CYP7A1, thereby negatively feedback inhibiting the de novo synthesis of BAs. These actions form together a negative feedback loop of BA homeostasis governed by the gut–liver axis [141].

In terms of mineral metabolism, FGF23 secreted by osteocytes is a key regulatory factor for phosphate and vitamin D homeostasis. Upon binding to the FGFR–Klotho complex at the distal convoluted tubule, FGF23 reduces the expression of the sodium‐phosphate cotransporters NaPi‐IIa and NaPi‐IIc, an effect that promotes phosphate excretion into the urine. Simultaneously, it also inhibits CYP27B1 expression, reducing the production of active vitamin D. Together, these actions jointly maintain the stability of blood phosphate levels [151, 152, 153]. Additionally, paracrine FGF1 is activated in adipose tissue under the transcriptional regulation of PPARγ. It facilitates adaptive remodeling of adipose tissue and augments mitochondrial oxidative phosphorylation (OXPHOS) activity via the FGFR1‐ERK1/2 signaling pathway, consequently improving the systemic insulin sensitivity. Collectively, these findings provide potential targets for therapeutic intervention in metabolic diseases [154].

Neural System Development

In addition to maintaining the body's metabolic homeostasis, FGF/FGFR signaling also plays a crucial regulatory role in neural system development. During the formation of synapses, FGF22 binds to presynaptic FGFR1b/FGFR2b receptors, which activates PI3K‐dependent signaling cascades that drive excitatory synaptic vesicle aggregation and subsequent assembly of functional excitatory synapses. In contrast, FGF7 functions through FGFR2b receptor engagement, where it diminishes inhibitory synaptic vesicle aggregation while simultaneously inhibiting synapse development [155]. Together, these two FGF ligands establish the balance of excitation and inhibition within local neural circuits.

For the development and maintenance of dopaminergic neurons within the substantia nigra, both FGF2 and FGF10 interact with FGFRs expressed on neuronal membranes, activating the PI3K/AKT and MAPK/ERK signaling pathways while suppressing mitochondrial‐mediated apoptosis to provide trophic support. Notably, FGF2 even reduces neuronal death in a 6‐hydroxydopamine injury model, demonstrating its potential neuroprotective effects [86].

It is worth noting that FGF11–FGF14, as non‐secreted intracellular proteins, modulate voltage‐gated sodium (Nav) channel inactivation kinetics along with axonal initial segment positioning via direct C‐terminal of Nav channel interactions. This interaction reduces overall neuronal excitability and influences action potential initiation [156, 157, 158]. For instance, loss of FGF14 leads to abnormal inactivation kinetics of Nav channels in cerebellar Purkinje cells, characterized by reduced membrane excitability and impaired firing rates; these electrophysiological alterations manifest as motor coordination deficits and ataxia phenotypes. In addition, FGF14 deficiency induces changes in the electrophysiological discharge pattern of hippocampal CA1 pyramidal neurons and compromises long‐term potentiation mechanisms at Schaffer collateral‐CA1 synapses. These disruptions contribute to spatial learning and memory deficits [159, 160]. Meanwhile, FGF13 regulates neuronal polarization and migration through its microtubule‐binding domain, which polymerizes tubulin and stabilizes microtubules [99].

Bone Development

Bone development and homeostasis are crucial for the proper functioning of the organism. As a key regulatory axis, FGF/FGFR signaling plays a multifaceted role in the skeletal system, not only promoting bone growth and development during the embryonic stage but also participating in maintaining bone homeostasis in adulthood.

During bone development, multiple FGF ligands exert distinct yet coordinated effects on chondrocytes. For instance, FGF2 inhibits excessive chondrocyte proliferation through activation of the STAT1 signaling pathway. FGF9 binding to FGFR3 induces MAPK and PI3K/AKT pathway activation, resulting in suppressed osteogenesis and enhanced osteoclast formation. Besides, FGF18, also through FGFR3 binding, upregulates Sox9 expression via activating the MAPK/ERK and STAT1 pathways. Through the above pathways, FGF18 inhibits excessive chondrocyte proliferation, while promoting their differentiation and matrix synthesis. Collectively, these three factors coordinately modulate chondrocyte proliferation, hypertrophy, and vascular invasion in long bones, thereby sustaining longitudinal bone growth [101, 161, 162]. Additionally, FGF23/FGFR1c signaling facilitates urinary phosphorus excretion and diminishes production of activated vitamin D, contributing to phosphorus homeostasis and indirectly regulating bone mineralization [163, 164].

Among FGFRs, FGFR3 serves as a critical negative regulator of chondrocyte proliferation in the growth plate. Gain‐of‐function mutations (such as G380R and G382D) lead to ligand‐independent, autonomous activation of FGFR3. This persistent activation continuously stimulates ERK signaling, which suppresses autophagy while promoting the HSPB6‐mediated ferroptosis pathway, ultimately eroding the stemness properties of resting zone chondrocytes and resulting in achondroplasia (ACH). Conversely, FGFR3 deficiency relieves this inhibition, leading to excessive bone growth [165, 166, 167]. Moreover, studies have demonstrated that FGFR3 deficiency leads to upregulation of matrix metalloproteinase‐13 (MMP13) and type X collagen expression in articular cartilage. This causes excessive degradation of proteoglycans and Type II collagen, chondrocyte hypertrophy, and diminished mechanical properties of articular cartilage, ultimately resulting in early arthritis‐like lesions and decreased bone density. These findings indicate that FGFR3 plays an important and sustained role in maintaining adult bone and joint health [168, 169].

Angiogenesis

Angiogenesis refers to the process of generating new blood vessels from the existing vascular network through the proliferation, migration, and lumen formation of endothelial cells, serving as an important basis for vascular system remodeling and expansion [170]. Within the regulatory network of angiogenesis, FGF/FGFR signaling is a key factor in both maintaining vascular homeostasis and inducing pathological angiogenesis.

FGF/FGFR signaling contributes to the maintenance of vascular tone and endothelial homeostasis. For example, FGF2 activates the FGFR‐ERK signaling pathway in endothelial cells, which then stimulates endothelial nitric oxide synthase (eNOS) expression via the AP‐1 transcription factor, enhancing nitric oxide (NO) biosynthesis and resulting in vasodilation [171]. Furthermore, activation of FGFR1 sustains homeostatic balance in endothelial cells by antagonizing TGF‐β/Smad signaling, which inhibits endothelial–mesenchymal transition (EndMT) and protects vascular function [172]. Following injury stimulation, FGFR1/2 on endothelial cells drives endothelial cell proliferation and migration through MAPK signaling cascade, facilitating neovascularization in response to tissue [173]. During angiogenesis, FGF2 directly activates the FGFR–MAPK pathway in endothelial cells to promote their proliferation and lumen formation, while simultaneously recruiting NG2+ pericytes and F4/80+ macrophages from bone marrow to build a pre‐vascular network. Subsequently, CD31+ endothelial cells infiltrate and cover this network, leading to the formation of mature blood vessels [174].

In addition to its roles under physiological conditions, FGF/FGFR signaling participates in the initiation and progression of various vascular diseases under pathological conditions. Within atherosclerotic plaques, FGF2 induces endothelial cell proliferation and migration by activating the FGFR–MAPK signaling and augments macrophage infiltration into the plaque. These actions drive intra‐plaque neovascularization and increase blood flow supply within the plaque [175, 176]. Additionally, abnormally elevated FGF23 activates the FGFR‐ERK and NF‐κB pathways in vascular cells and upregulates the synthesis of sulfated glycosaminoglycans (sGAG) and hyaluronic acid (HA). Subsequently, increased concentrations of sGAG and HA remodel the ECM and promote vascular calcification, hastening arteriosclerosis progression. Concurrently, FGF23 can directly act on cardiomyocytes to induce pathological myocardial hypertrophy [177, 178].

Within the tumor microenvironment (TME), FGFBP1 enhances the FGF2–FGFR1‐ERK1/2 signaling axis, which activates FAPα expression in hepatic stellate cells (HSCs). Then, activated HSCs promote EMT and the recruitment of immunosuppressive cells through the C‐X‐C motif chemokine ligand 5 (CXCL5)/C‐X‐C motif chemokine receptor 2 (CXCR2) signaling pathway. Consequently, these cascades mediate vascular co‐option and resistance to anti‐angiogenic therapy [179]. Furthermore, FGF2 upregulates platelet‐derived growth factor receptor (PDGFR) expression in endothelial cells, whereas platelet‐derived growth factor‐BB (PDGF‐BB) upregulates FGFR1 expression in mural cells, forming a bidirectional positive feedback loop that cooperatively promotes tumor angiogenesis and metastasis [180].

Aging

Aging is a progressive process characterized by the decline of tissue function and regenerative capacity, resulting from the combined effects of intrinsic and extrinsic factors [181, 182]. Emerging evidence indicates that FGF/FGFR signaling plays a pivotal role in regulating stem cell aging, tissue aging, as well as systemic aging.

FGF/FGFR signaling regulates the fate of adult stem cells through multiple mechanisms. For instance, in bone marrow mesenchymal stem cells (BMSCs), the effect of FGF2 on BMSC aging is dose‐dependent. Low levels of FGF2 promote BMSC mitotic activity via activation of the AKT and ERK pathways. However, chronic high‐dose FGF2 treatment results in ERK1/2 dephosphorylation, elevated LC3‐II‐mediated autophagy, and enhanced senescence‐associated β‐galactosidase (SA‐β‐gal) activity, ultimately causing BMSCs growth inhibition and accelerated senescence [183, 184]. In adipose tissue, excessive mitochondrial ROS downregulates the expression of CD90 in adipose stem cells (ASCs), leading to diminished glucose uptake and pentose phosphate pathway activity that culminates in ASC cell senescence. Conversely, FGF21 upregulates CD90 glycosylation and AKT‐GLUT4 axis activity, enhancing glucose influx and antioxidant capacity to ameliorate cellular senescence [185].

Moreover, age‐related dysregulation of FGF pathway can damage organ function. For example, FGF2 signaling is diminished in cranial osteoblasts with age, impairing osteogenic differentiation [177, 186]. Studies have shown that when leptin receptor‐positive bone stem cells undergo aging, leptin activates the STAT3 signaling pathway to upregulate FGF7 transcription. Subsequently, the elevated FGF7 promotes osteogenic differentiation of bone stem cells and inhibits osteoclastogenesis, leading to abnormal subchondral bone remodeling and accelerating the development of osteoarthritis (OA) [187]. In addition, the expression patterns of FGF2 and FGF7, as well as their receptors, change significantly during wound healing in aged mice, resulting in decreased fibroblast migration ability and delayed wound healing [96]. Additionally, aging reduces the proportion of FGF2‐expressing astrocytes in the hippocampus, diminishing FGFR1–MAPK/ERK signal and ultimately suppressing neural stem cell proliferation and cognitive decline [107].

Within the context of organismal aging, endocrine FGFs participate in systemic metabolic homeostasis and the aging process through their hormone‐like actions. For instance, FGF23 knockout mice exhibit hyperphosphatemia and excessive vitamin D due to upregulated expression of NaPi2a and 1α‐hydroxylase in the kidneys, presenting premature aging‐like phenotypes such as growth retardation, osteoporosis, vascular calcification, and multi‐organ atrophy. Notably, restoring FGF23 levels through genetic methods alleviates these premature aging‐like features, indicating that FGF23 delays systemic aging by regulating phosphorus and vitamin D metabolism [188]. Additionally, FGF19 also delays aging by regulating multiple metabolic pathways, reducing the risk of diabetes, obesity, and cardiovascular diseases [189]. KLB, which serves as a co‐receptor of FGF19/FGFR4, has been identified as a longevity protein that can extend lifespan, and its deficiency leads to aging‐like symptoms in humans, including shortened lifespan, skin atrophy, and infertility [190].

Immunoregulation

The immune system is a critical apparatus responsible for executing immune responses in the body. Composed of immune organs, immune cells, and immune molecules, it is tasked with identifying and eliminating foreign antigens, senescent cells, and mutant cells, while maintaining self‐tolerance and the stability of the internal environment [191]. The FGF/FGFR signaling family can influence the immune status of the tissue microenvironment by regulating the interaction between immune cells and stromal cells.

For instance, FGF1 activates the NF‐κB and NFAT pathways by binding to FGFR on the surface of T cells and cooperating with TCR signals, thereby promoting IL‐2 transcription and subsequently facilitating lymphocyte activation and proliferation [69]. In innate immunity, the role of FGF/FGFR signaling is more complex and even context‐dependent. For example, in rheumatoid arthritis (RA) and psoriasis, FGF2 cooperates with IL‐17 to promote inflammation by synergistically upregulating the expression of FGFR1 in target cells and enhancing the release of pro‐inflammatory factors like IL‐6 and IL‐8, an amplification loop that reinforces the Th17 cell‐mediated inflammatory response [192]. Conversely, in sepsis models, FGF21 exerts anti‐inflammatory effects by inhibiting the activation of inflammatory pathways in macrophages and promoting their transformation into anti‐inflammatory M2 phenotypes [193].

Furthermore, FGF/FGFR signaling also serves as a key bridge connecting cancer cells, stroma, and immune cells in the TME. For example, tumor‐derived FGF2 has been demonstrated to drive the polarization of tumor‐associated macrophages (TAMs) toward an M2‐like phenotype, accompanied by the secretion of immunosuppressive cytokines, including IL‐10 and TGF‐β [194]. Simultaneously, FGF2 has been shown to impair T cells’ adhesion and infiltration, while also restricting the cytotoxic function of CD8+ T cells, thereby collectively fostering an immunosuppressive TME [194]. In addition, elevated levels of FGF4 derived from triple‐negative breast cancer (TNBC) cells have been reported to activate the IL6/STAT3 signaling axis in macrophages, subsequently promoting their polarization into an immunosuppressive M2 phenotype. As a consequence, these polarized macrophages secrete IL‐10 and TGF‐β, which potently suppress the proliferation of CD8+ T cells, thus contributing to tumor immune escape [195].

Under normal circumstances, the FGF/FGFR signaling is strictly regulated and participates in the regulation of various cellular functions and physiological activities of the body through multiple mechanisms.