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Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism

Nature Metabolism volume 7, pages 2199–2211 (2025)Cite this article

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Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease or NAFLD) is a prevalent and heterogeneous condition affecting nearly 30% of the global population. MASLD is defined as excessive hepatic lipid accumulation with at least one feature of insulin resistance, with potential progression to metabolic dysfunction-associated steatohepatitis, cirrhosis and hepatocellular carcinoma. The disease often coexists with insulin resistance and cardiovascular and chronic kidney diseases. Human genetics has shed light on MASLD predisposition and its causal association with type 2 diabetes and insulin resistance, enabling the field to progress towards precision-medicine therapeutics. Convergent selection of somatic mutations in genes involved in glucose and lipid metabolism in cirrhotic livers suggests adaptive responses to gluco-lipotoxicity that influence end-stage liver disease. Recently, two distinct types of MASLD, with specific clinical trajectories, were identified on the basis of partitioned polygenic risk scores. Future studies are needed to integrate this knowledge, enabling earlier detection, risk stratification and targeted therapies.

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Fig. 1: Human genetics of MASLD.
Fig. 2: Cirrhosis evolution.
Fig. 3: Precision-medicine framework for patient stratification in SLD.
Fig. 4: Different clinical trajectories in systemic MASLD and liver-specific MASLD.

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Acknowledgements

S.R. was supported by the Swedish Cancerfonden (22 2270 Pj), the Swedish Research Council (Vetenskapsradet (VR), 2023-02079), the Swedish state under the Agreement between the Swedish government and the county councils (the ALF agreement, ALFGBG-965360), the Swedish Heart Lung Foundation (20220334), the Novo Nordisk Distinguished Investigator Grant - Endocrinology and Metabolism (NNF23OC0082114), the Novo Nordisk Project grants in Endocrinology and Metabolism (NNF24OC0091535) and AstraZeneca Agreement for Research. L.V. was supported by the Italian Ministry of Health (Ministero della Salute), Ricerca Finalizzata 2021 RF-2021-12373889, Italian Ministry of Health, Ricerca Finalizzata PNRR 2022 ‘RATIONAL: Risk stratification of nonalcoholic fatty liver’ PNRR-MAD-2022-12375656, the European Union, H2020-ICT-2018-20/H2020-ICT-2020-2 programme ‘Photonics’ under grant agreement No. 101016726 – REVEAL, the European Union, HORIZON-MISS-2021-CANCER-02-03 programme ‘Genial’ under grant agreement ‘101096312’, the Italian Ministry of Research (MUR) PNRR – M4 - C2 ‘National Center for Gene Therapy and Drugs based on RNA Technology’ CN3, Spoke 4 ‘ASSET: A sex-specific approach to NAFLD targeting’, and the PRIN 2022 MUR: ‘Disentangling genetic, epigenetic and hormonal regulation of Fe/heme metabolism in the gender-specific nature of NAFLD (DEFENDER)’. The funders had no role in the present work.

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Authors and Affiliations

  1. Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy

    Rosellina M. Mancina

  2. Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Rosellina M. Mancina & Stefano Romeo

  3. Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy

    Rosellina M. Mancina

  4. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Luca Valenti

  5. Precision Medicine – Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Luca Valenti

  6. Department of Medicine (H7), CeRM Karolinska Institute, Huddinge, Sweden

    Stefano Romeo

  7. Department of Endocrinology, Karolinska University Hospital, Huddinge, Sweden

    Stefano Romeo

  8. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Stefano Romeo

  9. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy

    Stefano Romeo

Authors
  1. Rosellina M. Mancina
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  2. Luca Valenti
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Contributions

All authors contributed to the content and organization of this Review; to writing, editing and/or revising the manuscript; and approved the final version.

Corresponding authors

Correspondence to Rosellina M. Mancina, Luca Valenti or Stefano Romeo.

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Competing interests

S.R. received the research grant from AstraZeneca for basic-science research on steatotic liver disease and has been consulting for AstraZeneca, GSK, Celgene Corporation, Ribo-cure AB¸ Ultragenyx, Amgen, Sanofi, Wave Life Sciences, Novartis, Chiesi and Pfizer in the past 5 years; declares equity in Heptabio; and is an inventor on a patent titled “Method for treating fatty liver disease”, on PSD3, US application number 17,480266 filed on 21 September 2021. L.V. has been consulting for Novo Nordisk, Pfizer, Boehringer Ingelheim, Resalis, MSD and speaker for Viatris, Novo Nordisk, GSK. R.M.M. has nothing to declare.

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Nature Metabolism thanks Stefan Stender, Michele Vacca and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Yanina-Yasmin Pesch, in collaboration with the Nature Metabolism team.

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Mancina, R.M., Valenti, L. & Romeo, S. Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism. Nat Metab 7, 2199–2211 (2025). https://doi.org/10.1038/s42255-025-01394-8

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