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Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Abstract
The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.
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“As such, it is an important therapeutic target of protection against muscle and liver insulin resistance induced by lipids and DM2 [106,107].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [106]
In the citing paper
“Substances that act as adipokines, myokines, and hepatokines, such as FGF21, are essential for controlling glucose and lipid metabolism.”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [106]
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“Based on the findings that interference with FGFR1c blocked the homeostatic regulation of BW by increased loading and that circulating liver-derived FGF21 decreases BW via central FGFR1c-b-Klotho signaling (21–25), we next evaluated the effect of increased loading on three endocrine FGFs: FGF15, FGF21, and FGF23, whic…”
BackgroundFibroblast Growth Factors as Tools in the Management of Neuropathic Pain Disorders
Forouzanfar, F., & Sadeghnia, H. R. (2020) · Current Drug Targets · doi:10.2174/1389450121666200423084205 · Cited by 7
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What’s So Special about FGF19—Unique Effects Reported on Skeletal Muscle Mass and Function
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Fibroblast growth factor 21 is related to cisplatin resistance in ovarian cancer
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“Fibroblast growth factor 21 (FGF21) is a recently described regulatory factor expressed in liver, adipose tissue, muscle, and pancreatic b cells.(11,12) Because it lacks a heparin-binding domain, FGF21 is secreted into the circulation to exert an endocrine-like function.”
BackgroundBahijri, S., Eldakhakhny, B. M., Enani, S. M., Ajabnoor, G., Al-Mowallad, A. S., Alsheikh, L., Alhozali, A. M., Alamoudi, A. A., Borai, A., & Tuomilehto, J. O. (2023) · Cureus · doi:10.7759/cureus.50524 · Cited by 6
“Fibroblast growth factor 21 (FGF-21) appears to be a likely candidate for investigation as it has been reported to be engaged in the inter-organ endocrine signaling axes, which are pertinent for the maintenance of the entire-body homeostasis as they govern the metabolism and homeostasis [14,15].”
BackgroundThyroid Hormones Regulate Goblet Cell Differentiation and Fgf19-Fgfr4 Signaling
Blitz, E., Matsuda, H., Günther, S., Morikawa, T., Kubota, Y., Zada, D., Lerer‐Goldshtein, T., Stainier, D. Y. R., & Appelbaum, L. (2021) · Endocrinology · doi:10.1210/endocr/bqab047 · Cited by 6
Decreased serum fibroblast growth factor 19 level is a risk factor for type 1 diabetes
Hu, J., Tang, Y., Liu, H., Li, Y., Li, X., Huang, G., Xiao, Y., & Zhou, Z. (2021) · Annals of Translational Medicine · doi:10.21037/atm-20-5203 · Cited by 5
“In addition, FGF19 can inhibit the activity of cAMP regulatory element-binding protein (CREB) to downregulate glucose synthesis in mice (23,25).”
BackgroundZhang, Y., Luo, J.-X., Li, Y.-G., Fu, H., Yang, F., & Hu, X.-Y. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/4583645 · Cited by 6
“In particular, fibroblast growth factor (FGF) 21 is considered a potential therapeutic target for a variety of chronic human diseases, including obesity and type 2 diabetes mellitus [12].”
Smith, V. A. O., Jiang, Y., Thymann, T., Sangild, P. T., Maj, M. A., Manjarín, R., & Burrin, D. G. (2020) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000002645 · Cited by 6
“Fibroblast growth factor 19 (FGF19) is a key FXR target gene whose secretion is triggered by luminal Bas, and functions as an intestinal endocrine hormone (8).”
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Chronic High Phosphate Intake in Mice Affects Macronutrient Utilization and Body Composition
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Better end points needed in primary sclerosing cholangitis trials
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“FGF1 induces cell proliferation mainly via FGFR3 and FGFR4, while its metabolic activity is predominantly mediated by FGFR1 (Degirolamo et al., 2016; Suh et al., 2014; Wu et al., 2011).”
Antúnez-Rodríguez, A., García-Rodríguez, S., Pozo-Agundo, A., Sánchez-Ramos, J. G., Escobar, E. M., Triviño-Juárez, J. M., Martínez-González, L. J., & Dávila-Fajardo, C. L. (2024) · Thrombosis Research · doi:10.1016/j.thromres.2024.109060 · Cited by 4
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Physiological and pathophysiological role of endocrine fibroblast growth factors
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The early and late intervention effects of collagen-binding FGF2 on elastase-induced lung injury.
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Saponins from Panax japonicus Enhance Lipolysis via Acting on FGF21-β-Klotho/FGFR1 in Obese Mice
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Fibroblast growth factor and kidney disease: Updates for emerging novel therapeutics
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Fibroblast growth factor 19 stimulates water intake
Bedoya, J. U., Chavey, C., Desandré, G., Meunier, L., Dupuy, A., Dopeso‐Reyes, I. G., Tordjmann, T., Assénat, E., Hibner, U., & Grégoire, D. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101483 · Cited by 5
“com promising therapeutic targets for several diseases [12].”
BackgroundRijal, G. (2021) · Bioengineering · doi:10.3390/bioengineering8110163 · Cited by 4
“Fibroblast growth factors like FGF1, FGF15, 19 & 21 have emerged as key regulators of carbohydrate and lipid metabolism [96,97].”
BackgroundA novel monovalent FGFR1 antagonist: Preclinical safety profiles in rodents and non-human primates
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FGF (Fibroblast Growth Factor)
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Hamroun, A., Boukrout, N., Cauffiez, C., Fellah, S., der Hauwaert, C. V., Pottier, N., Mentaverri, R., Zaworski, J., Gnemmi, V., Gibier, J., et al. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae307 · Cited by 3
“The choice of FGF19 is justified by its structural proximity to the FGF subfamily of soluble endocrine proteins and its hepatic expression in the context of acute hepatitis [18 ].”
BackgroundTakahara, K., Ouchi, N., Takikawa, T., Ozaki, Y., Fang, L., Kawanishi, H., Tatsumi, M., Yura, Y., Kato, K., Takefuji, M., et al. (2025) · Physiological Reports · doi:10.14814/phy2.70135 · Cited by 3
Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism
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Increased FGF-19 levels following explantation in women with breast implant illness
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“Specifically, it stimulates phosphate excretion and inhibits the formation of 1,25(OH)2D3, the active form of vitamin D (1,25 dihydroxycholecalciferol) ([27]).”
BackgroundFGF13 suppresses acute myeloid leukemia by regulating bone marrow niches
Li, R., Xue, K., & Li, J. (2022) · Frontiers of Medicine · doi:10.1007/s11684-022-0944-z · Cited by 3
FGF19 and muscle architecture in older patients
Bres, É., Bouvier, J., Courtay, A., Delaire, L., Humblot, J., Cuerq, C., Tripoz-dit-Masson, S., Fauvernier, M., Gilbert, T., & Bonnefoy, M. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112120 · Cited by 4
“Endocrine fibroblast growth factors (FGF) regulate numerous metabolic signaling pathways and are involved in maintaining whole-body homeostasis (Degirolamo et al., 2016; Beenken and Mohammadi, 2012).”
BackgroundCurrent and Emerging Treatments for Non-alcoholic Steatohepatitis
Horn, C. L., Ta, A. C., & Gunn, N. (2020) · Current Hepatology Reports · doi:10.1007/s11901-020-00540-y · Cited by 3
Chiba, A., & Mochizuki, N. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813814-4.00014-6 · Cited by 3
Krones, E., & Wagner, M. (2016) · Hepatology · doi:10.1002/hep.28691 · Cited by 3
“Binding to FGFR4/b-klotho activates ERK and other downstream kinases,((1)) which is particularly important for the repressive effects on bile acid synthesis as the effects are lost when FGFR4 or b-klotho is eliminated or ERK is inhibited.”
BackgroundInfluentialYun, Z., Zhang, K., Zhang, Y., He, P., & Wang, Z. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1635234 · Cited by 4
Interorgan crosstalk in metabolic dysfunction-associated steatotic liver disease
Yang, R., Fang, Z., He, F., & Wang, L. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003927 · Cited by 2
Jarzabek, J., Jaczynska, M., Kasprzak, Z., Zakrzewska, M., & Sałaga, M. (2026) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2026.106989 · Cited by 2
Bile acid signaling: from dynamic pool composition to inter-organ communication
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“Additionally, gut-derived FGF15/19 activates the b -klotho/FGFR complex in the hypothalamus, boosting energy expenditure and improving glucose tolerance (92).”
Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response
Nandakumar, M., Moin, A. S. M., Ramanjaneya, M., Al‐Qaissi, A., Sathyapalan, T., Atkin, S. L., & Butler, A. E. (2022) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14716 · Cited by 2
“FGF19 is a postprandial insulin-independent protein that regulates hepatic protein and glycogen synthesis and is involved in lipid and energy metabolism.(72) Lower levels of FGF19 have been reported in newly diagnosed patients with T2D, FGF19 having a close relationship to β-cell function, as indicated by the insulin…”
BackgroundFibroblast Growth Factor 21 as a Regulator of Energy Metabolism in the Liver and Adipose Tissue
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Cai, R., Liu, Z., Feng, Z., Qin, M., Li, J., Zhao, Q., & He, X. (2024) · Organ medicine. · doi:10.1002/orm2.8 · Cited by 2
Novel FGF21 analogues through structure-based optimization for therapeutic development
Guo, Y., Bao, Y., Chen, Z., Rao, Z., Luo, Y., Ye, S., & Liu, S. (2024) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2024227 · Cited by 2
“However, its limited pharmacokinetic property and biological potency remain significant challenges for its clinical application [26 ‒ 29].”
Upregulation of hypothalamic POMC neurons after biliary diversion in GK rats
Zhou, S., Chen, W., Bai, X., Chen, J., Xu, Q., Dong, L., Chen, W., Qu, Q., & He, X. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.999928 · Cited by 2
“FGF15/19, as an intestinal hormone, has been shown to regulate glucose homeostasis (47) by binding to FGF receptors and the coreceptor Klotho, which are located in different tissues, such as the liver (48), adipose tissue (49), and the brain (50).”
BackgroundWadsley, J., Christie, A., Gillmore, R., Trinh, A., & Greig, R. (2023) · Drugs in Context · doi:10.7573/dic.2023-5-5 · Cited by 2
Gut microbiota and nonalcoholic fatty liver disease
Kim, B., & Kim, B. K. (2023) · Kosin Medical Journal · doi:10.7180/kmj.23.138 · Cited by 2
FGF (Fibroblast Growth Factor)
Katoh, M. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_313 · Cited by 2
Proceedings of the 2020 Classic Examples in Toxicologic Pathology XXVII
Nolte, T., Baumgärtner, W., Colbatzky, F., Knippel, A., Marxfeld, H., Nehrbass, D., Odin, M., Popp, A., Treumann, S., Yen, H.-Y., et al. (2021) · Toxicologic Pathology · doi:10.1177/01926233211019288 · Cited by 1
“Hyperphosphatemia as seen in both FGF23- and a-klotho-deficient animals can promote senescence, ectopic calcification, and chronic kidney disease (CKD).(57) Dr Knippel emphasized that although FGF23 plays a central role in mineral homeostasis, the overall interactions are much more orchestrated with various factors in…”
BackgroundIntestinal and Renal Adaptations to Changes of Dietary Phosphate Concentrations in Rat
Lucea, S., Chopo‐Escuin, G., Guillén, N., Sosa, C., & Sorribas, V. (2023) · Function · doi:10.1093/function/zqad063 · Cited by 1
“17 , 18 However, the intestine contains PTH receptors that could be inv olv ed in some of the adaptation mechanisms.”
BackgroundGeng, L., Yi, X., Lin, Y., Abulimiti, X., Jin, L., Yu, J., & Xu, A. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.138846 · Cited by 2
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BOZKURT, A., Kara, E., Bulut, F. D., Kaplan, İ., Burgaç, E., Köşeci, B., Gündüz, N. T., Dağlıoğlu, G., Şeydaoğlu, G., Mungan, N. Ö., et al. (2025) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2025-0255 · Cited by 1
Circulating Molecular Drivers of Bone Remodeling in Pancreatitis
Hill, R. L., Yadav, D., Hart, P. A., Whitcomb, D. C., McQuerry, K., Karnik, K. N., Stello, K. M., Conwell, D. L., & Rao, M. (2025) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000926 · Cited by 1
“FGF23 plays a role in phosphate metabolism and bone mineralization (53 – 55), while oncostatin has been implicated in osteoclast and osteoblast regulation (56 – 58).”
Chetana, S., & Kalyani, B. (2025) · Cardiovascular Toxicology · doi:10.1007/s12012-025-10079-3 · Cited by 1
“…that DCM patients have significantly lower plasma BCAA levels than type 2 diabetic patients without cardiomyopathy, also BCAA deficiency worsens cardiomyopathy by activating autophagy in car - diac fibroblast, while BCAA supplementation is protective [ 164], thus severe BCAA restriction may cause…”
ZHANG, B., Li, Y., FAN, P., & WANG, S. (2026) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b25-00528 · Cited by 1
Patent Highlights December 2016–January 2017
Mucke, H. A. (2017) · Pharmaceutical Patent Analyst · doi:10.4155/ppa-2017-0007 · Cited by 1
Non-alcoholic Fatty Liver Disease - New Insight and Glance Into Disease Pathogenesis
Kang, S. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.100998 · Cited by 1
Serum Fibroblast Growth Factor 19 as a Biomarker in Hepatitis B Virus-Related Liver Disease
Miao, X., Wu, G., An, X., Guo, X., & Peng, C. (2022) · Hepatitis Monthly · doi:10.5812/hepatmon-130652 · Cited by 1
“Inclusion criteria included (1) age is between 18 and 75 years with no gender limitation; (2) CHB is defined as patients with positive HBsAg for at least six months or HBV DNA > 2,000 IU/mL, which also requires serological or histopathological evidence, excluding cirrhosis and liver tumors; (3) HBV-cirrhosis is define…”
BackgroundEmerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis
Iwaki, M., Yoneda, M., Wada, N., Otani, T., Kobayashi, T., Nogami, A., Saito, S., & Nakajima, A. (2024) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2024.2328036 · Cited by 1
“On the other hand, FGF21 is a hepatokine secreted from the liver, and unlike FGF19, its effects are exerted via the FGFR1c/ βKlotho complex [58].”
BackgroundTreatments of nonalcoholic fatty liver disease in adults who have no other illness: A Review article
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Discovery, Structural Refinement and Therapeutic Potential of Farnesoid X Receptor Activators
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Effective medical treatments for PSC needed ASAP - is AESOP the answer?
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“FGF21 is released from the liver of fasting rodents and humans to promote adipose “browning” (mitochondrial uncoupling to promote heat generation (6)).”
BackgroundCorneal Endothelium Regeneration: Future Prospects
Ho, W., Liu, H.-Y., Hu, F., & Wang, I. (2019) · Essentials in ophthalmology/Essentials ophthalmology · doi:10.1007/978-3-030-01304-2_31
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The role of gastrointestinal hormones in the pathogenesis and the treatment of obesity
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“Therefore, the use of FRX receptor agonists, and induction of FGF-19 production, as a form of obesity therapy may prove to be an effective and non-invasive method of treating this metabolic disorder (26).”
MethodSerum Fibroblast Growth Factor 19 As A Predictor and Follow Up of Hepatocellular Carcinoma
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“Table (3):- CHILD class between CLD and HCC groups CLD HCC Total X(2) P”
BackgroundMethodInfluentialThe hormone Fibroblast Growth Factor 19 stimulates water intakePreprint
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“They are released from the extracellular matrix and reach remote target organs through the bloodstream.(9) A remarkable structural feature of FGF19 subfamily members is the presence of an additional C-terminal loop protruding from the β-trefoil core structure.”
BackgroundResearch Progress of Fibroblast Growth Factor 23 and Cognitive Impairment
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Pathopysiologie: Insulinresistenz
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Therapeutic Approach to NAFLD-NASH
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Klotho Protein and Type 2 Diabetes Mellitus
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“Fibroblast growth factor 21 (FGF-21) is an endocrine hormone capable of improving metabolic dysfunction and related complications by regulating the energy balance (Degirolamo et al., 2016; BonDurant and Potthoff, 2018; Geng et al., 2020).”
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Endocrine fibroblast growth factors in domestic animals
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“Because of the high metabolism of cancer cells, they may suffer nutrient starvation, which may explain the increased FGF21 levels in patients with more consistent PTC (22).”
Association of cerebrospinal fluid FGF21 with sleep quality in Chinese adults
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Main Types of Fibroblast Growth Factors: Biological Functions and Significance
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Metadata
- Authors
- Degirolamo, C., Sabbà, C., & Moschetta, A.
- Affiliations
- Istituto Tumori Bari (IT)
- University of Bari Aldo Moro (IT)
- Corresponding author
- Moschetta, Antonio
- Venue
- Nature Reviews Drug Discovery
- Published
- 2015-11-16
- Volume
- 15
- Issue
- 1
- Pages
- 51-69
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2214871873
- Cited by
- 424
- References
- 240
- Citations by year
- 2026: 21 · 2025: 30 · 2024: 36 · 2023: 42 · 2022: 55 · 2021: 48 · 2020: 54 · 2019: 43 · 2018: 41 · 2017: 36 · 2016: 18
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Keywords
- FGF19, FGF21, fibroblast growth factor 23, bile acid metabolism, glucose metabolism, lipid metabolism, vitamin D homeostasis, phosphate homeostasis, obesity, type 2 diabetes, cancer, kidney disease, cardiovascular disease
- MeSH terms
- Fibroblast Growth Factor-23, Animals, Chronic Disease, Fibroblast Growth Factors, Homeostasis, Humans, Models, Biological, Drugs, Investigational
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