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FGF-based drug discovery: advances and challenges

Nature Reviews Drug Discovery volume 24, pages 335–357 (2025)Cite this article

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Abstract

The fibroblast growth factor (FGF) family comprises 15 paracrine-acting and 3 endocrine-acting polypeptides, which govern a multitude of processes in human development, metabolism and tissue homeostasis. Therapeutic endocrine FGFs have recently advanced in clinical trials, with FGF19 and FGF21-based therapies on the cusp of approval for the treatment of primary sclerosing cholangitis and metabolic syndrome-associated steatohepatitis, respectively. By contrast, while paracrine FGFs were once thought to be promising drug candidates for wound healing, burns, tissue repair and ischaemic ailments based on their potent mitogenic and angiogenic properties, repeated failures in clinical trials have led to the widespread perception that the development of paracrine FGF-based drugs is not feasible. However, the observation that paracrine FGFs can exert FGF hormone-like metabolic activities has restored interest in these FGFs. The recent structural elucidation of the FGF cell surface signalling machinery and the formulation of a new threshold model for FGF signalling specificity have paved the way for therapeutically harnessing paracrine FGFs for the treatment of a range of metabolic diseases.

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Fig. 1: HSPGs define mode of FGF action.
Fig. 2: FGFs act in endocrine or paracrine fashion.
Fig. 3: FGFR signal transduction units and signalling cascade.
Fig. 4: The threshold model for FGFR signalling specificity and its potential application in FGF-based drug discovery.
Fig. 5: Strategies to therapeutically harness FGF21.

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Acknowledgements

This work was supported by the Kunpeng Action Plan Award (to M.M.), National Natural Science Foundation for International Senior Scientists (32350710196 to M.M.), National Natural Science Foundation of China (82073705 & 82273842 to G.C., 82422068 to L.C.), National Key R&D Program of China (2017YFA0506000 to X.L.), Oujiang laboratory startup fund (OJQD2022007 to M.M.) and Natural Science Funding of Zhejiang Province (LR22H300002 & DG25H300001 to G.C., LR24H300001 & DG25H300002 to L.C.).

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  1. These authors contributed equally: Gaozhi Chen, Lingfeng Chen.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Gaozhi Chen & Xiaokun Li

  2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Lingfeng Chen

  3. Institute of Cell Growth Factor, Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health, Wenzhou, Zhejiang, China

    Moosa Mohammadi

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All authors actively participated in examining and analysing existing literature, designing and discussing the content of the manuscript. M.M., G.C., and L.C. wrote and edited the manuscript. L.C. generated the figures. All authors reviewed and approved the final manuscript before publication.

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Chen, G., Chen, L., Li, X. et al. FGF-based drug discovery: advances and challenges. Nat Rev Drug Discov 24, 335–357 (2025). https://doi.org/10.1038/s41573-024-01125-w

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