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Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH)

Nature Reviews Drug Discovery volume 24, pages 171–189 (2025)Cite this article

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

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Fig. 1: Responses for major clinical trials in MASH.
Fig. 2: Major systemic effects of FGF-21R and GLP-1R agonists.
Fig. 3: THRβ, PPARα and glucagon agonists act on hepatocytes.
Fig. 4: The central fatty acid synthesis pathway.
Fig. 5: Desirable functional changes in MASH.

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Acknowledgements

We are grateful to B. Banini, V. Gupta and J. Dranoff for their helpful comments during manuscript preparation. W.Z.M. is supported by a VA Merit Award.

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  1. Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Albert Do, Frhaan Zahrawi & Wajahat Z. Mehal

  2. Division of Gastroenterology, University of California, Davis, Davis, USA

    Albert Do

  3. West Haven Veterans Hospital, West Haven, CT, USA

    Wajahat Z. Mehal

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Do, A., Zahrawi, F. & Mehal, W.Z. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 24, 171–189 (2025). https://doi.org/10.1038/s41573-024-01084-2

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