Fibroblast Growth Factor (FGF): A Comprehensive Reference
1. Identity: Nomenclature, Chemical Nature, and Natural Sources
1.1 Nomenclature and Chemical Classification
Fibroblast growth factors (FGFs) are a family of polypeptide signaling proteins unified by conserved structural characteristics rather than by a single shared biological function. Although the first fibroblast growth factor was discovered as a mitogen on 3T3 fibroblasts, the name is functionally misleading, as this group of secreted proteins — now consisting of 22 members — was assembled based on common structural characteristics rather than functional similarity, and only a few members strictly act on fibroblasts. FGFs are polypeptide growth factors with diverse biological activities. The mammalian FGF family comprises 22 members, which can be classified as intracellular FGFs (iFGFs), canonical FGFs, and hormone-like FGFs (hFGFs) by their mechanisms of action.
The FGF family comprises 22 known isoforms (ligands), classified into seven subfamilies — FGF1, FGF4, FGF7, FGF8, FGF9, FGF15/19, and FGF11 — and four transmembrane tyrosine kinase FGF receptors (FGFRs). The two most historically studied members are FGF1 (acidic FGF, aFGF) and FGF2 (basic FGF, bFGF), which were the first to be isolated and characterized. FGF is roughly classified by isoelectric point into two types: basic FGF (bFGF) and acidic FGF (aFGF).
The broader family includes several members of particular biomedical interest:
- FGF1 (aFGF) — acidic fibroblast growth factor; paracrine/autocrine acting
- FGF2 (bFGF) — basic fibroblast growth factor; the most extensively studied member in wound healing and tissue repair
- FGF7 (KGF, keratinocyte growth factor) — primarily acts on epithelial cells
- FGF19 — an endocrine-acting member regulating bile acid and glucose metabolism
- FGF21 — an endocrine hormone regulating lipid, glucose, and energy metabolism
- FGF23 — an endocrine hormone regulating phosphate and vitamin D homeostasis
Endocrine FGFs — specifically FGF19, FGF21, and FGF23 — constitute a subfamily of FGFs secreted in the circulation with roles in bile acid, glucose, and lipid metabolism (FGF19); metabolic adaptation during fasting (FGF21); and modulation of vitamin D and phosphate homeostasis (FGF23).
1.2 Protein Structure
The structural domains of FGFs are well conserved, and the core region of the protein consists of 12 β-sheets. FGF21, similar to other FGFs of the endocrine subfamily, lacks a heparin-binding site. In contrast, paracrine FGFs (such as FGF1 and FGF2) do contain heparin-binding domains. FGF23 is a 32 kDa polypeptide with an N-terminal and a C-terminal region with 251 amino acids.
1.3 Natural Sources
FGFs are endogenous proteins produced by a wide range of human and animal tissues. Both the brain and the pituitary gland have been known to contain mitogenic factors for cultured cells; in 1974, the identification in the pituitary gland of a growth factor called fibroblast growth factor was reported. Pituitary extract is a known source of fibroblast growth factor (FGF), and FGF is known to stimulate growth of mononucleate muscle cells from various mammals and to inhibit their differentiation.
Specific members have distinct tissue origins. FGF23 is a phosphaturic hormone secreted mainly by osteocytes and osteoblasts in bone but also expressed by salivary glands, stomach, and, in much lower concentrations, by other tissues, including skeletal muscles, brain, mammary gland, liver, and heart. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas. FGF15/19 (mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption.
In contrast to other tissues, only four FGFs — FGF2, FGF7, FGF10, and FGF21 — are dominant in the skin.
1.4 Preparations and Forms
FGFs for research, clinical, and cosmetic use are produced in several ways. FGFs in the narrower sense include natural FGFs especially of bovine and human origin, as well as FGFs prepared recombinantly; particularly preferred are human aFGF and bFGF prepared recombinantly. Recombinant human FGF2 (rhFGF2) and recombinant bovine bFGF (rb-bFGF) are the forms most commonly encountered in clinical literature. Topical gels, solutions, and spray formulations of recombinant bFGF have been approved and used clinically in countries such as Japan and China.
2. Historical and Traditional Context
2.1 Scientific Discovery
FGFs were first identified in the 1970s as key mediators in wound healing and tissue regeneration. Until 1974, the mitogenic factors present in the brain and pituitary gland were of unclear relationship to classical pituitary hormones; in 1974, the identification in the pituitary gland of a growth factor called fibroblast growth factor (FGF) was reported by Gospodarowicz in the journal Nature. FGF was first separated as a factor exhibiting strong growth-promoting action on fibroblasts such as BALB/c-3T3 cells.
The first human recombinant FGF-2 was reported in 1988. Topical recombinant FGF2 has been approved in Japan for the treatment of skin ulcers since 2001. Discovered in 2000, fibroblast growth factor 21 (FGF21) is a peptide hormone of the endocrine FGF subfamily, along with FGF23 and FGF15/19.
2.2 Traditional Use of FGF-Modulating Plants
Fibroblast growth factor as a purified, isolated molecule is entirely a modern scientific construct with no traditional use in itself. However, plants used for centuries in traditional medicine are now understood to modulate endogenous FGF activity. While FGF as a purified ingredient is a relatively recent discovery, its medicinal benefits have deep roots in traditional remedies, particularly those focused on enhancing the body's regenerative processes. This important distinction separates the traditional use of FGF-modulating botanicals from the scientific study of FGF proteins themselves.
In terms of the supplement landscape, FGF is positioned as a bioactive ingredient in the context of skin health, tissue repair, and metabolic regulation — applications grounded entirely in modern molecular biology rather than ethnobotanical tradition.
3. Key Constituents and Active Compounds
3.1 The FGF Family: A Molecular Overview
FGFs are a family of multifunctional cell signaling proteins with a wide variety of regulatory, morphological, and endocrine effects on multiple cell types. They function as pluripotent growth factors and play a role in the normal development of animal cells and in tumor metastasis and angiogenesis.
The 22 FGFs can be classified as intracellular (intracrine), paracrine (canonical), and endocrine (hormone-like) FGFs by their mechanisms of action. Paracrine FGFs mediate biological responses by binding to and activating cell surface tyrosine kinase FGF receptors (FGFRs). Intracrine FGFs (FGF11–FGF14) are not secreted extracellularly and instead function inside cells to modulate voltage-gated sodium channels and other intracellular targets.
The endocrine subfamily — FGF19, FGF21, and FGF23 — acts systemically via the bloodstream and requires co-receptors (α-Klotho or β-Klotho) to bind their respective FGFRs. Metabolic FGFs consist of FGF15/19, FGF21, and FGF23.
3.2 FGF Receptors (FGFRs)
The family of FGF receptors (FGFR1-4) are receptor tyrosine kinases expressed on cell membranes with significant sequence homology. Each FGFR typically consists of three extracellular immunoglobulin-like domains, a hydrophobic transmembrane domain, and two intracellular tyrosine kinase domains.
The FGF-FGFR complex consists of two receptor molecules, two FGFs, and a heparan sulfate proteoglycan (HSPG); the HSPG stabilizes and sequesters the FGFs. Ligand specificity of FGFR is regulated by alternative splicing within the C-terminal half of the third Ig loop in the ligand-binding domain. Ligand binding and FGFR dimerization trigger kinase domain phosphorylation, which leads to the docking of adapter residues and the activation of downstream pathways.
4. Mechanisms of Action
4.1 Canonical (Paracrine) Signaling
FGF and FGFR binding stimulates receptor dimerization, an interaction that can be stabilized by heparan sulfate proteoglycans (HSPGs). FGF-FGFR binding further phosphorylates intracellular FGFR substrate 2 (FRS2), phospholipase C gamma (PLCγ), and JAK, thereby activating four major signaling pathways. Activation of FRS2 recruits the adaptor proteins GRB2 and SOS, resulting in subsequent activation of MAPK. GRB2 also recruits GAB1, which leads to activation of the PI3K-AKT-mTOR pathway.
Phosphorylation of PLCγ hydrolyzes PIP2 to IP3 and DAG, thus activating protein kinase C (PKC); JAK-STAT signaling can also be activated. These four principal downstream pathways — RAS-MAPK, PI3K-AKT, PLCγ/PKC, and JAK-STAT — collectively regulate cell proliferation, survival, migration, differentiation, and angiogenesis.
Stable binding of FGFs to their receptor tyrosine kinases (RTKs) and signaling requires the presence of heparan sulfate (HS) or heparin. The assembly of a ternary signaling complex comprising two FGFs, two RTK molecules, and HS is made possible by HS-binding motifs on both the FGF ligand and on the RTK.
4.2 Endocrine (Hormone-Like) Signaling: FGF21 and FGF23
Endocrine FGFs signal differently. Unlike paracrine FGFs, FGF21, similar to other FGFs of the endocrine subfamily, lacks a heparin-binding site, allowing it to circulate freely in the bloodstream. As an endocrine hormone, FGF21 plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle.
For FGF23, FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its co-receptor Klotho. While FGF23 can activate FGFR3 and FGFR4, FGFR1c appears to be the primary endocrine receptor for FGF23.
4.3 FGF2 in Tissue Repair
Fibroblast growth factor 2 (FGF2), also called basic FGF, has the potential to accelerate wound closure by activating vascular endothelial cells and fibroblasts. Extensive laboratory studies have demonstrated FGFs' ability to stimulate the proliferation of fibroblasts, which are cells responsible for synthesizing extracellular matrix and collagen. Consistent with its ability to stimulate the proliferation of bovine and vascular endothelial cells, FGF has similar activity in vivo on capillary endothelial cells; therefore, FGF is considered an angiogenic factor.
FGF plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation, and cell migration. In addition to fibroblasts, FGF is also mitogenic for a wide variety of normal diploid mesoderm-derived and neural crest-derived cells, including granulocytes, adrenal cortical cells, chondrocytes, myoblasts, corneal and vascular endothelial cells, vascular smooth muscle cells, and lens epithelial cells.
5. Scientific Evidence by Area of Use
5.1 Wound Healing and Skin Repair
This is the area with the strongest clinical evidence base for FGF application, particularly for FGF2 (bFGF). Fibroblast growth factor 2 (FGF2), a potent mediator of cellular proliferation, angiogenesis, and extracellular matrix remodeling, has emerged as a promising therapeutic agent in burn care; a systematic review evaluated the biological mechanisms, delivery strategies, and clinical outcomes associated with FGF2 in burn wound healing to clarify its therapeutic value and translational potential.
Thirty-three studies from 1992–2025 met inclusion criteria, encompassing randomized controlled trials, animal models, and mechanistic analyses. FGF2 accelerated repair by stimulating fibroblast proliferation, keratinocyte migration, angiogenesis, and matrix organization. Topical FGF2 formulations shortened healing time and improved scar quality in partial-thickness burns.
Administration of recombinant FGF2 to skin wounds accelerates acute and chronic wound healing. Topical recombinant FGF2 has been approved in Japan for the treatment of skin ulcers since 2001.
Growth factor products including FGF have been used for decades, although no systematic evaluation existed regarding their effectiveness and safety issues in treating acute skin wounds, resulting in a lack of guidelines and standards for proper application regimes.
In diabetic and complex burn models, FGF2 mitigated inflammation, preserved barrier integrity, and promoted re-epithelialization. Efficacy depended on dosage and wound characteristics. Studies reported favorable safety profiles with minimal and mild adverse events.
A 2026 prospective randomized controlled trial examined recombinant bovine bFGF (rb-bFGF) in hair transplantation: sixty patients with moderate-to-severe androgenetic alopecia were randomly assigned to either an rb-bFGF group or a control group; in the rb-bFGF group, harvested follicles were intraoperatively immersed in an rb-bFGF-enriched solution and patients received postoperative topical rb-bFGF gel for 3 weeks. The rb-bFGF group demonstrated superior outcomes, including higher 12-month follicle survival (91.1% vs. 81.0%), lower hair-loss rate (11.6% vs. 22.7%), greater patient satisfaction (96.7% vs. 80.0%), and fewer complications (20.0% vs. 85.3%), with all differences statistically significant (p < 0.001).
Evidence strength: Moderate to strong for topical FGF2 in wound healing and burn care (supported by multiple RCTs and systematic reviews). Regulatory approval in Japan lends additional weight. Evidence for supplemental oral FGF in wound healing is absent from the reviewed literature.
5.2 Metabolic Syndrome, Obesity, and Diabetes (FGF21)
Under obesity-related metabolic disorder conditions, systemically administered FGF21 has been shown to induce sustained weight loss, lower blood glucose and triglyceride levels, improve insulin sensitivity, increase brown adipocyte numbers, preserve β-cell function and mass. In obese rodents, FGF21 causes weight loss and improves insulin sensitivity without causing hypoglycemia or decreasing food intake; it also decreases triglyceride and cholesterol levels.
Several human clinical trials have been reported with long-acting FGF21 analogs. These trials have used engineered analogs rather than native FGF21 because of the poor pharmacokinetic and biophysical characteristics of native FGF21, prompting the development of long-acting FGF21 analogs and FGF21 receptor agonists for the treatment of metabolic dysfunction.
A 2024 systematic review and meta-analysis of human clinical trials found: The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids, or systolic blood pressure. However, treatment significantly reduced fasting insulinemia, body weight, and total cholesterolemia. None of the included studies were at high risk of bias. The quality of evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.
Phase 2 clinical data on pegbelfermin (PGBF), a PEGylated recombinant analog of human FGF21: Pegbelfermin has a prolonged half-life that supports up to weekly dosing. In a phase 2 clinical study, PGBF was proved safe and well tolerated in patients with obesity and type 2 diabetes treated daily or weekly for 12 weeks. Treatment significantly improved serum HDL, triglycerides, adiponectin, and Pro-C3.
Regarding glycemic effects, FGF21 treatment improved glycemic control in diet-induced obese mice; however, this effect did not seem to translate as convincingly to humans, while an increase in insulin sensitivity has been observed.
Dietary substances have been shown to modulate endogenous FGF21. Betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating FGF21 levels. Betaine fails to improve metabolic health in mice lacking FGF21, demonstrating that FGF21 is required for the beneficial effects of betaine. This is evidence in mice only; direct human trial data for this mechanism are not established in the reviewed literature.
In human subjects, plasma FGF21 level was shown to be increased dramatically following 28 days on a low-protein diet.
Evidence strength: Moderate clinical evidence for engineered FGF21 analogs (not native FGF21 or dietary supplements) in reducing body weight and triglycerides in humans. Evidence for direct FGF21 protein supplementation is limited to pharmaceutical-grade analogs investigated in phase 1/2 trials. Dietary modulation of endogenous FGF21 is primarily animal-model evidence.
5.3 Liver Disease: Non-Alcoholic Steatohepatitis (NASH) and Fatty Liver
FGF21 has been shown to reduce hepatic steatosis through increased fatty acid oxidation and decreased lipogenesis in rodents. An FGF21 analogue has been shown to reduce inflammation and fibrogenesis in a NASH mouse model. In a phase 2 trial, a protracted FGF21 reduced liver fat, liver injury, and fibrosis biomarkers in NASH patients.
In a phase IIa trial, patients with stage 1–3 NASH were treated with PGBF at a dose of 10 mg daily or 20 mg weekly subcutaneous injection for 16 weeks.
An engineered variant of FGF19 (aldafermin) has also been tested in NASH. Aldafermin was tested in several clinical trials involving patients receiving the molecule subcutaneously during 12 or 24 weeks for NASH without cirrhosis, primary sclerosing cholangitis, primary biliary cholangitis, or bile acid diarrhea; these first trials generated mixed results.
Evidence strength: Preliminary to moderate (phase 2 clinical trials). Promising signals for NASH biomarkers, but no approved drug exists for this indication as of the time of writing. Evidence pertains to pharmaceutical analogs, not commercially available dietary supplements.
5.4 Mineral Metabolism, Bone, and Kidney (FGF23)
FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism, and α-klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH, and reduces circulating 1,25(OH)₂D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)₂D.
FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis. In patients with chronic kidney disease, circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone.
Multiple studies have shown that FGF23 levels increase in the very early stages of chronic kidney disease (CKD), and its concentration may also be highly associated with cardiac complications. FGF23 is considered both an early and sensitive marker for CKD-related bone disease and a novel and potent cardiovascular risk factor.
The effects of FGF23 are most evident in rare diseases characterized by FGF23-mediated hypophosphatemic rickets-osteomalacia. More commonly, elevated FGF23 is an early consequence of CKD in which it helps to maintain normal serum phosphate levels but causes secondary hyperparathyroidism by suppressing 1,25D, and directly promotes cardiovascular disease and death.
Evidence strength: Well-established (strong) for FGF23's physiological role in phosphate and vitamin D regulation; strong clinical evidence for its use as a biomarker in CKD and cardiovascular risk. FGF23 itself is not used as a therapeutic supplement but is a biomarker of clinical importance.
5.5 Bile Acid Metabolism and Gastrointestinal Physiology (FGF19)
FGF19 and its murine ortholog Fgf15 are the founding members of the endocrine FGF subfamily. FGF19 and Fgf15 influence a variety of metabolic processes including glucose, lipid, and bile acid metabolism, as well as gallbladder filling. FGF19 is a postprandial enterokine induced by the nuclear hormone receptor Farnesoid X Receptor (FXR) upon activation by bile acids.
The recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose, and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family.
Circulating levels of FGF19 were found to be reduced in individuals with obesity and comorbidities such as type 2 diabetes and metabolic dysfunction–associated fatty liver disease.
Evidence strength: Mechanistic understanding of FGF19's role in bile acid regulation is well established in human physiology. Clinical trial evidence for therapeutic FGF19 analogs is preliminary and mixed (phase 2). FGF19 is not a commercially available dietary supplement.
5.6 Neuroscience and Mood (FGF2)
A broader view of the role of the FGF family in modulating brain function has been proposed; some FGF ligands together with FGF receptors are altered in individuals with affective disorder and modulate emotionality in animal models.
Members of the FGF family may be genetic predisposing factors for anxiety, depression, or substance abuse; they play a key organizing role during early development but continue to play a central role in neuroplasticity in adulthood. The FGF family appears to be a prototype of "switch genes" endowed with organizational and modulatory properties across the lifespan, potentially representing molecular candidates as biomarkers and treatment targets for affective and addictive disorders.
Evidence strength: Preliminary; most evidence is from animal models and post-mortem human brain studies. No clinical trials of FGF supplementation for mood or neurological disorders in humans are cited in the reviewed literature.
5.7 Cardiovascular Disease
The protective effect of FGF21 against atherosclerosis has been demonstrated in preclinical trials. One study carried out on apoE-/- mice indicated that the administration of recombinant human FGF21 can protect against atherosclerotic plaque formation.
However, there have been no clinical trials on the application of FGF21-based drugs in CVD treatment, and most clinical trials have investigated the application of FGF21 in metabolic diseases.
Having strong growth-promoting action and plasminogen activator–inducing action on endothelial cells, FGFs are expected to have potential applications as angiogenesis promoters and as therapeutic drugs for trauma, thrombosis, and arteriosclerosis.
Evidence strength: Preclinical only for direct cardiovascular FGF therapy. FGF23 elevation is a well-validated cardiovascular risk marker in CKD patients, but therapeutic interventions remain investigational.
5.8 Diabetic Wound Healing (FGF1, 2, 7, 21, 23)
Researchers have been applying FGF-1, FGF-2, FGF-4, FGF-7, FGF-21, and FGF-23 topically to diabetic foot ulcers with good therapeutic effects; this review elaborates on the recently developed FGF family members, outlining their mechanisms of action and describing their potential therapeutics in diabetic foot ulcers.
Evidence strength: Moderate for topical clinical use in diabetic wounds, though the field continues to develop standardized protocols.
6. Body Systems and Health Areas of Association
Based on the peer-reviewed literature, the FGF family is associated with the following body systems and physiological domains:
- Integumentary system: Wound healing, scar repair, skin regeneration, hair follicle biology (FGF1, FGF2, FGF7)
- Metabolic system: Glucose homeostasis, lipid metabolism, insulin sensitivity, obesity (FGF21)
- Hepatic/gastrointestinal system: Bile acid regulation, fatty liver disease, steatohepatitis (FGF19, FGF21)
- Renal and skeletal system: Phosphate homeostasis, vitamin D metabolism, bone mineralization, CKD-mineral bone disorder (FGF23)
- Cardiovascular system: Angiogenesis, endothelial function, atherosclerosis risk (FGF2, FGF21, FGF23)
- Nervous system: Neuroplasticity, affective behavior, neurotrophic support (FGF2)
- Embryonic development: Tissue patterning, organogenesis (FGF3, FGF4, FGF8, FGF10, and others)
- Musculoskeletal system: Chondrocyte and myoblast growth, adrenal cortical function (FGF1, FGF2)
Research firmly established FGFs as key players in development, morphogenesis, angiogenesis, hematopoiesis, and survival; in addition, FGF19, FGF21, and FGF23 have been shown to be involved in glucose, lipid, bile acid, phosphate, and vitamin D metabolism.
7. Dosage Forms and Reported Dosages
The dosage forms and amounts reported in peer-reviewed clinical literature are for pharmaceutical-grade recombinant proteins, not over-the-counter dietary supplements. There are currently no established dosages for orally consumed FGF supplements, as intact FGF proteins are subject to proteolytic degradation in the gastrointestinal tract; topical and injectable forms constitute the studied delivery routes.
- Topical recombinant bFGF (wound healing): The first randomized, blinded, placebo-controlled human trials of recombinant basic FGF for pressure sore treatment tested three different concentrations of bFGF in five dosing schedules for safety, including hematology, serum chemistry, and urinalysis assessments. Specific concentration details were not disclosed in the abstract.
- Topical rb-bFGF (hair transplantation): Harvested follicles were intraoperatively immersed in an rb-bFGF-enriched solution and patients received postoperative topical rb-bFGF gel for 3 weeks. Precise concentration was not specified in the source.
- Pegbelfermin / PGBF (NASH, obesity, T2DM — subcutaneous injection): In a phase 2 clinical study, PGBF was tested daily or weekly for 12 weeks and significantly improved serum HDL, triglycerides, adiponectin, and Pro-C3. In another phase IIa trial, patients with stage 1–3 NASH were treated with PGBF at a dose of 10 mg daily or 20 mg weekly subcutaneous injection for 16 weeks.
No orally bioavailable FGF dietary supplement dosage has been validated in human clinical trials reviewed in this article. Topical formulations approved in Japan and China are applied directly to wound surfaces and are classified as therapeutic agents, not dietary supplements, in those jurisdictions.
8. Safety Considerations and Interactions
8.1 Oncogenic Potential
The most significant and well-documented safety concern with exogenous FGF activity is its potential to promote tumor development. FGF signaling regulates cell proliferation, differentiation, survival, angiogenesis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis continues to emerge.
Animal models have suggested that aberrant FGF signaling can promote tumor development through increased cell proliferation and survival as well as increased tumor angiogenesis. FGF signaling is an important pathway in tumorigenesis and tumor angiogenesis.
FGF proteins have been implicated in promoting tumorigenesis in carcinomas and sarcomas by promoting tumor vascularization and as transforming proteins when their expression is deregulated.
For FGF19 specifically: At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. This has prompted efforts to engineer FGF19 analogs (such as aldafermin) designed to uncouple metabolic benefits from hepatocyte proliferative risk. Many FGF19 targets have a dual function in both metabolism and cell proliferation, challenging the development of FGF19-variants that fully uncouple metabolic benefit from mitogenic potential.
8.2 Topical FGF Safety Profile
Efficacy of FGF2 in wound healing depended on dosage and wound characteristics; studies reported favorable safety profiles with minimal and mild adverse events.
8.3 Pharmaceutical FGF21 Analog Safety
Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. These findings pertain to engineered pharmaceutical analogs given subcutaneously and do not directly translate to unregulated supplemental forms.
8.4 FGF23 Elevation as a Pathological Risk Factor
Elevated FGF23 is an early consequence of CKD in which it helps maintain normal serum phosphate levels but causes secondary hyperparathyroidism by suppressing 1,25D and directly promotes cardiovascular disease and death. Therefore, interventions that chronically elevate FGF23 may be deleterious in individuals with compromised kidney function.
8.5 FGFR Inhibitor Adverse Events (Pharmacological Context)
While not directly applicable to supplemental FGF use, the adverse event profile observed when FGF signaling is pharmacologically manipulated offers insight into the pathway's importance. FGFR inhibitors give rise to adverse events affecting the skin, including the more common nail adverse events (e.g., onycholysis), palmar-plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis.
8.6 Important Biological Distinctions for the Supplement Context
A fundamental scientific consideration for any dietary supplement claiming to deliver FGF activity is the protein nature of FGFs. As polypeptides, FGF proteins are susceptible to proteolytic digestion in the gastrointestinal tract upon oral administration. The peer-reviewed literature identifies no established mechanism by which intact, biologically active FGF proteins survive oral ingestion to exert systemic effects. All clinical evidence reviewed here involves topical application, subcutaneous injection, or intravenous administration of recombinant or engineered analogs. This does not prevent products from being marketed, but the scientific basis for orally consumed FGF supplements acting via direct FGF receptor activation has not been demonstrated in human studies.
References
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