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Targeting metabolic dysregulation for fibrosis therapy

Nature Reviews Drug Discovery volume 19, pages 57–75 (2020)Cite this article

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Abstract

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development — such as the activation of transforming growth factor-β and the deposition of extracellular matrix — have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.

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Fig. 1: Disease burden of fibrosis.
Fig. 2: TGFβ signalling pathway.
Fig. 3: Major metabolic pathways involved in fibrosis and antifibrosis drug targets.
Fig. 4: Collagen production and degradation.

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Acknowledgements

The authors thank Lisa Chong for producing the figures. The authors are funded in part by the Canadian Institutes of Health Research, Genome Canada, the Canadian Cancer Society Research Institute, the Physicians Services Incorporated Foundation, the Harry Barberian Research Scholarship, the Mariano Elia Chair in Head and Neck Cancer Research, the Peter and Shelagh Godsoe Chair in Radiation Medicine, the Princess Margaret Cancer Centre Head and Neck Translational Program, the Princess Margaret Cancer Centre Radiation Medicine Program and the Ottawa Heart Institute Research Corporation, as well by philanthropic funding from the Jesse Rasch Foundation, the Wharton family, Joe’s Team and the Ministry of Health and Long-Term Care. The views expressed in the publication are the views of the authors and do not necessarily reflect those of the Ministry of Health and Long-Term Care.

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  1. Xiao Zhao

    Present address: Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada

    Xiao Zhao & Fei-Fei Liu

  2. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

    Xiao Zhao, Jennifer Yin Yee Kwan & Fei-Fei Liu

  3. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Jennifer Yin Yee Kwan & Fei-Fei Liu

  4. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

    Jennifer Yin Yee Kwan & Fei-Fei Liu

  5. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Kenneth Yip & Fei-Fei Liu

  6. University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    Peter P. Liu

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Glossary

Anaerobic glycolysis

The metabolism of glucose to lactate when insufficient oxygen is present.

Aerobic glycolysis

The metabolism of glucose to lactate via glycolysis when sufficient oxygen is present.

Fibrocytes

Circulating mesenchymal cells that express vimentin and produce extracellular matrix molecules such as collagen.

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Zhao, X., Kwan, J.Y.Y., Yip, K. et al. Targeting metabolic dysregulation for fibrosis therapy. Nat Rev Drug Discov 19, 57–75 (2020). https://doi.org/10.1038/s41573-019-0040-5

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