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Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23

Degirolamo, Chiara, Sabbà, Carlo, Moschetta, Antonio·2016·Nature Reviews Drug Discovery

DOI 10.1038/nrd.2015.9

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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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Background
The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy
Deng, J., Liu, Y., Liu, Y., Li, W., & Nie, X. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s334996 · Cited by 28
Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Montgomery, M. K., Bayliss, J. A., Nie, S., Nardo, W. D., Keenan, S. N., Miotto, P. M., Karimkhanloo, H., Huang, C., Schittenhelm, R. B., Don, A. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28889-2 · Cited by 33
Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance
Li, M., Qian, M., & Xu, J. (2017) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00051 · Cited by 29
“Endocrine fibroblast growth factors (FGFs), such as FGF21, FGF15/19, and FGF23, are critical for maintaining whole-body homeostasis, because they operates in inter-organ endocrine signaling pathways that govern glucose, bile acid, and lipid metabolism (54, 55).”
Background
Implications of Fibroblast Growth Factors (FGFs) in Cancer: From Prognostic to Therapeutic Applications
Dianat‐Moghadam, H., & Teimoori‐Toolabi, L. (2019) · Current Drug Targets · doi:10.2174/1389450120666190112145409 · Cited by 28
The gut–liver axis in hepatocarcinoma: a focus on the nuclear receptor FXR and the enterokine FGF19
Piglionica, M., Cariello, M., & Moschetta, A. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.08.005 · Cited by 30
Multiple faces of fibroblast growth factor-23
Han, X., & Quarles, L. D. (2016) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000240 · Cited by 28
“duced by hepatocytes in the liver, targets adipoctyes to regulate fat and energy metabolism [13,14].”
Background
Fibroblast growth factor 21 ameliorates vascular calcification by inhibiting osteogenic transition in vitamin D3 plus nicotine-treated rats
Shi, Y., Lu, W., Hou, Y.-L., Fu, K., Gan, F., & Liu, J. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.10.115 · Cited by 27
Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease
Chikamatsu, M., Watanabe, H., Shintani, Y., Murata, R., Miyahisa, M., Nishinoiri, A., Imafuku, T., Takano, M., Arimura, N., Yamada, K., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.01.039 · Cited by 27
Ursodeoxycholic acid exerts hepatoprotective effects by regulating amino acid, flavonoid, and fatty acid metabolic pathways
Kim, D. J., Chung, H., Ji, S. C., Lee, S., Yu, K., Jang, I., & Cho, J. (2019) · Metabolomics · doi:10.1007/s11306-019-1494-5 · Cited by 27
Fibroblast Growth Factor Binding Protein 3 (FGFBP3) impacts carbohydrate and lipid metabolism
Tassi, E., Garman, K. A., Schmidt, M. O., Ma, X., Kabbara, K. W., Üren, A., Tomita, Y. A., Goetz, R. M., Mohammadi, M., Wilcox, C. S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-34238-5 · Cited by 28
FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis
Lang, L., Xiong, Y., Prieto‐Domínguez, N., Loveless, R., Jensen, C., Shay, C., & Teng, Y. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01888-9 · Cited by 26
Metformin treatment for 8 days impacts multiple intestinal parameters in high-fat high-sucrose fed mice
Bravard, A., Gérard, C., Defois, C., Benoit, B., Makki, K., Meugnier, E., Rainteau, D. P., Rieusset, J., Godet, M., & Vidal, H. (2021) · Scientific Reports · doi:10.1038/s41598-021-95117-0 · Cited by 28
Stimuli-responsive hydrogel with spatiotemporal co-delivery of FGF21 and H₂S for synergistic diabetic wound repair
Chu, L., Shen, J., Xu, Z., Huang, J., Ning, L., Feng, Z., Jiang, Y., Wu, P., Gao, C., Wang, W., et al. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113749 · Cited by 26
A novel role for farnesoid X receptor in the bile acid‐mediated intestinal glucose homeostasis
Zhao, L., Xuan, Z., Song, W., Zhang, S., Li, Z., Song, G., Zhu, X., Xie, H., Zheng, S., & Song, P. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15881 · Cited by 26
FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes
Yanucil, C., Kentrup, D., Li, X., Grabner, A., Schramm, K. J., Martinez, E. C., Li, J., Campos, I. D., Czaya, B. A., Heitman, K., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-11033-x · Cited by 25
Fibroblast Growth Factor 23 and Muscle Wasting: A Metabolic Point of View
Afşar, R. E., Afşar, B., & Ikizler, T. A. (2023) · Kidney International Reports · doi:10.1016/j.ekir.2023.04.027 · Cited by 25
“Majority of FGFs act as autocrine and paracrine proteins (canonical FGFs) with 4 tyrosine kinase receptors [FGF receptor (FGFR) 1–4)].(13) They bind FGFRs with quite low affinity and require transmembrane glycoproteins, a-klotho and b-klotho, as coreceptors in their respective tissues to activate their cognate FGFRs.”
BackgroundInfluential
Implications of FGF19 on sorafenib-mediated nitric oxide production in hepatocellular carcinoma cells - a short report
Gao, L., Shay, C., Lv, F., Wang, X., & Teng, Y. (2017) · Cellular Oncology · doi:10.1007/s13402-017-0354-4 · Cited by 25
FGF9 inhibits browning program of white adipocytes and associates with human obesity
Sun, Y., Wang, R., Zhao, S., Li, W., Liu, W., Tang, L., Wang, Z., Wang, W., Liu, R., Ning, G., et al. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0151 · Cited by 25
Fibroblast Growth Factor Family in the Progression of Prostate Cancer
Teishima, J., Hayashi, T., Nagamatsu, H., Shoji, K., Shikuma, H., Yamanaka, R., Sekino, Y., Goto, K., Inoue, S., & Matsubara, A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8020183 · Cited by 29
“Several studies have demonstrated the physiological function of endocrine FGFs (Table 1) [4].”
Background
Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects
Watanabe, H., Miyahisa, M., Chikamatsu, M., Nishida, K., Minayoshi, Y., Takano, M., Ichimizu, S., Kobashigawa, Y., Morioka, H., Maeda, H., et al. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.05.036 · Cited by 24
Endocrine Fibroblast Growth Factors in Relation to Stress Signaling
Shimizu, M., & Sato, R. (2022) · Cells · doi:10.3390/cells11030505 · Cited by 25
“Furthermore, endocrine FGFs may play certain roles in metabolic disorders; hence, these polypeptides have become attractive target molecules for the development of therapies [19].”
Background
Ablation of FGFR2 in Fibroblasts Ameliorates Kidney Fibrosis after Ischemia/Reperfusion Injury in Mice
Xu, Z., & Dai, C. (2017) · Kidney Diseases · doi:10.1159/000484604 · Cited by 24
Fibroblast growth factor 21 regulates glucose metabolism in part by reducing renal glucose reabsorption
Li, S., Wang, N., Guo, X., Li, J., Zhang, T., Ren, G., & Li, D. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.09.078 · Cited by 25
Oleic Acid Attenuates Ang II (Angiotensin II)-Induced Cardiac Remodeling by Inhibiting FGF23 (Fibroblast Growth Factor 23) Expression in Mice
Liu, T., Wen, H., Li, H., Xu, H., Xiao, N., Liu, R., Chen, L., Sun, Y., Song, L., Bai, C., et al. (2020) · Hypertension · doi:10.1161/hypertensionaha.119.14167 · Cited by 24
“FGF23 binding to its receptor led to phosphorylation of PLCγ (phospholipase Cγ), which promoted expression of numerous transcription factors via the Ca-dependent pathway, including NFAT1, MEF2, and SRF, and those factors have a close relationship with cardiac integrity, pathological remodeling, and cardiac hypertrophy…”
Background
Dynamic folding modulation generates FGF21 variant against diabetes
Zhu, L., Zhao, H., Liu, J., Cai, H., Wu, B., Liu, Z., Zhou, S., Liu, Q., Li, X., Bao, B., et al. (2020) · EMBO Reports · doi:10.15252/embr.202051352 · Cited by 23
Experimental and Investigational Targeted Therapies for the Management of Fibrosis in NASH: An Update
Huisman, T. M., Dieterich, D. T., & Friedman, S. L. (2021) · Journal of Experimental Pharmacology · doi:10.2147/jep.s265286 · Cited by 22
FGF19 is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits Lung Fibrosis in Mice
Justet, A., Ghanem, M., Boghanim, T., Hachem, M., Vasarmidi, E., Jaillet, M., Vadel, A., Joannes, A., Mordant, P., Bonniaud, P., et al. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2021-0246oc · Cited by 26
Metformin promotes cholesterol efflux in macrophages by up-regulating FGF21 expression: a novel anti-atherosclerotic mechanism
Luo, F., Guo, Y., Ruan, G., & Li, X. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0281-9 · Cited by 23
“tissue, is a novel metabolic regulator with multiple cardioprotective efficacy [19].”
Background
The FGF/FGFR signalling mediated anti-cancer drug resistance and therapeutic intervention
Mahapatra, S., Jonniya, N. A., Koirala, S., Ursal, K., & Kar, P. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2191721 · Cited by 19
“…in various developmental processes like wound repair, angiogenesis, organ development, etc. FGFR-FGF-Heparin ternary complex (Figure 3E) regulates body homeostasis, bile acid production, metabolic pathways of glucose and lipids, maintenance of vitamin D levels, and more (Degirolamo et al., 2016).”
Background
Circulating Fibroblast Growth Factor 19 in Portal and Systemic Blood
Johansson, H., Mörk, L.-M., Li, M., Lövgren‐Sandblom, A., Björkhem, I., Höijer, J., Ericzon, B., Jorns, C., Gilg, S., Sparrelid, E., et al. (2017) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2017.07.001 · Cited by 22
“The half-life of FGF19 has been observed to approximately 30 min and it has been speculated that circulating FGF19 is cleared through the kidneys considering its small size (21 kDa).(20) Bile acids are the primary inducer of FGF19 via activation of FXR, which was emphasized here by a strong association between the tot…”
Background
The Enterokine Fibroblast Growth Factor 15/19 in Bile Acid Metabolism
Cariello, M., Piglionica, M., Gadaleta, R. M., & Moschetta, A. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_235 · Cited by 22
Surgery-Induced Weight Loss and Changes in Hormonally Active Fibroblast Growth Factors: a Systematic Review and Meta-Analysis
Hosseinzadeh, A., Roever, L., & Alizadeh, S. (2020) · Obesity Surgery · doi:10.1007/s11695-020-04807-7 · Cited by 22
FGF19 protects against obesity-induced bone loss by promoting osteogenic differentiation
Guo, A., Li, K., Tian, H., Tao, B., Xiao, Q., & Jiang, D. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112524 · Cited by 21
Glycosylation of FGF/FGFR: An underrated sweet code regulating cellular signaling programs
Gędaj, A., Gregorczyk, P., Żukowska, D., Chorążewska, A., Ciura, K., Kalka, M., Porębska, N., & Opaliński, Ł. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.04.001 · Cited by 22
Characterisation of endogenous players in fibroblast growth factor‐regulated functions of hypothalamic tanycytes and energy‐balance nuclei
Kaminskas, B., Goodman, T. H., Hagan, A. S., Bellusci, S., Ornitz, D. M., & Hajihosseini, M. K. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12750 · Cited by 22
“The remaining FGFs (11-14) function intracellularly in a receptor-independent manner (8).”
Background
Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets
Chu, Y., Yang, S., & Chen, X. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108844 · Cited by 21
Hypoxia-Induced Adipose Lipolysis Requires Fibroblast Growth Factor 21
Wu, G., Liu, Y., Feng, W., An, X., Lin, W., & Tang, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01279 · Cited by 20
“FGF21 is a member of the FGF superfamily and is a potential metabolic regulator (Degirolamo et al., 2016; Kliewer and Mangelsdorf, 2019; Lewis et al., 2019).”
Background
Liver-Secreted Hexosaminidase A Regulates Insulin-Like Growth Factor Signaling and Glucose Transport in Skeletal Muscle
Montgomery, M. K., Bayliss, J. A., Nie, S., Nardo, W. D., Keenan, S. N., Anari, M., Taddese, A. Z., Williamson, N. A., Ooi, G., Brown, W. A., et al. (2022) · Diabetes · doi:10.2337/db22-0590 · Cited by 22
Low circulating concentrations of citrulline and FGF19 predict chronic cholestasis and poor survival in adult patients with chronic intestinal failure: development of a Model for End-Stage Intestinal Failure (MESIF risk score)
Koelfat, K. V. K., Huijbers, A., Schaap, F. G., van Kuijk, S. M. J., Martin Lenicek, A., Soeters, M. R., Wanten, G. J. A., & Damink, S. W. M. O. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz036 · Cited by 20
“0001 Intestinal dysmotility (n = 49) 39 [32, 51] NS 4 [3, 11] NS 120 [50, 366] <0.”
Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies
Gerussi, A., D’Amato, D., Cristoferi, L., O’Donnell, S. E., Carbone, M., & Invernizzi, P. (2019) · Annals of Hepatology · doi:10.1016/j.aohep.2019.09.009 · Cited by 20
“Fibroblast growth factor (FGF)19 is a hormone induced in the gut y FXR, and acts in the liver by suppressing CYP7A1, the enzyme hat catalyses the first rate-limiting step in the classic pathway f bile acids synthesis [5,16,17].”
Background
Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation
Gollowitzer, A., Pein, H., Rao, Z., Waltl, L., Bereuter, L., Loeser, K., Meyer, T., Jafari, V., Witt, F., Winkler, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56711-2 · Cited by 21

Authors: Degirolamo, C., Sabbà, C., & Moschetta, A.
Affiliations: Istituto Tumori Bari (IT)
University of Bari Aldo Moro (IT)
Corresponding author: Moschetta, Antonio
ORCID: Sabbà, Carlo
Moschetta, Antonio
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2015-11-16
Volume: 15
Issue: 1
Pages: 51-69
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd.2015.9
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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Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23

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