Fibrosis: from mechanisms to medicines

Abstract

Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.

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Fig. 1: Deconvolving fibrosis using multi-modal single-cell approaches.
Fig. 2: Functional heterogeneity and plasticity of fibroblasts.
Fig. 3: Metabolomic reprogramming of activated fibroblasts.
Fig. 4: Divergent cytokine pathways drive fibrosis.
Fig. 5: Challenges and solutions in the translation of antifibrotic mechanisms into drugs.

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Acknowledgements

N.C.H. is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z), the Medical Research Council, a Chan Zuckerberg Initiative Seed Network Grant, the British Heart Foundation and Tenovus Scotland. F.R. is supported by grants from the National Institutes of Health (T32DK083251, P30DK097948 Pilot, K08DK110415 and R01DK123233), the Crohn’s and Colitis Foundation, the Cleveland Clinic, the Rainin Foundation and the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium.

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N.C.H., F.R. and T.A.W contributed equally to the writing and editing of all aspects of this review.

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Correspondence to Thomas A. Wynn.

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N.C.H. has received research funding from AbbVie, Pfizer, Gilead and Galecto, and is an advisor or consultant for Galecto, Indalo Therapeutics, Pliant Therapeutics, GSK and Boehringer-Ingelheim. F.R. is an advisor or consultant for AbbVie, Allergan, BMS, Boehringer-Ingelheim, Celgene, Falk Pharma, Gilead, Genentech, Gossamer, GSK, Receptos, Thetis, UCB, Samsung, Koutif, Pliant Therapeutics, Metacrine, Takeda, Theravance, Pfizer, Agomab, Helmsley, RedX and Roche. T.A.W. is employed by Pfizer.

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Henderson, N.C., Rieder, F. & Wynn, T.A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020). https://doi.org/10.1038/s41586-020-2938-9

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