Abstract
Alcoholic liver disease (ALD) remains a significant clinical challenge with limited therapeutics. It is strongly associated with sarcopenia, which further worsens the prognosis in liver cirrhosis. Zinc-deficiency is a hallmark of ALD, impairing the liver’s antioxidant defenses and alcohol metabolism. Here we identify a chaperone role for MG53/TRIM72 in facilitating crosstalk between zinc and alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2), acting as a metabolic regulator of muscle-liver communication. In ALD, muscle-derived MG53 is transported to liver and mitigates liver damage. MG53 deficiency exacerbates hepatic zinc-deficiency and impairs ADH and ALDH2 activity, which are reversed by systemic administration of recombinant human MG53 (rhMG53). MG53’s B-box motif coordinates zinc interaction with ADH and ALDH2, enhancing their enzymatic activity to clear toxic alcohol byproducts. We developed a bio-derived nanoparticle for co-delivery of rhMG53 and zinc, offering a promising therapeutic approach for ALD. In vivo findings are applicable to the male sex only.
Data availability
National Health and Nutrition Examination Survey (NHANES) data were obtained from the available dataset at https://wwwn.cdc.gov/nchs/nhanes/Default.aspx. Original data for creating all graphs in the paper are provided in Source data 1. A public dataset of liver proteomics for ALD patients that supports the findings of this study is available in the HUMAN LIVER PROTEOME DATABASE (http://www.liverproteome.org/). Liver mass spectrometry data for ALD patients from our hospital center have been deposited in ProteomeXchange with the primary accession code PXD058395 (https://www.iprox.cn/page/home.html). Human skeletal muscle-specific proteins, secreted proteins, and normal liver-detected mRNA lists that support the findings of this study are available in the Human Protein Atlas (https://www.proteinatlas.org/). Original data for creating all graphs in the paper are provided in Source data 2 and 3. All the source data are provided with this paper. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Source data are provided with this paper.
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Acknowledgements
This work was supported in part by the Major Science and Technology Projects in Yunnan Province (202302AA310041, 202403AC100021) to C.Z. and J.W., the National Natural Science Foundation of China (82470299, 82460021) to Y.H. and Y.Y., US National Institutes of Health (R01 AG072430, R01EY036243) to J.M., and Open Project of the Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research Ministry of Education of China (KFKT202501) and Postdoctoral Innovative Talent Support Program (ZXBSH032) to T.S. We are deeply indebted to Xiaoyang Wang from the Army Medical University for her expert technical support in the realm of proteomics, and we would like to thank all the participants and professionals contributing to the NHANES, HUMAN LIVER PROTEOME DATABASE, and Human Protein Atlas.
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C.Z., Y.H., and J.M. conceptualized and designed the study, supervised the overall project, and participated in text revision. T.S. and X.Z. performed experiments, analyzed data, designed figures, and drafted the manuscript. J.W. participated in statistical analyses, text writing, and revising. H.J. constructed a nanoparticle, participated in animal imaging, and performed fluorescence labeling and big data analyses. Y.W., M.Z., P.C., J.X., and N.L contributed to clinical samples and information gathering from patients. B.H. and D.F. established the animal model system and performed pathological staining. L.J., Y.J., and L.Z. participated in animal model establishment, mass spectrometry analysis, and cell culture. L.Y. performed mass spectrometry analysis of human samples. M.T. and Y.Y. participated in animal observation and data gathering. K.L., Y.C., J.K., and R.L. participated in data analyses and manuscript writing.
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Shu, T., Zeng, X., Wang, J. et al. MG53 mediates skeletal muscle-liver cross-talk and enhances alcohol metabolism in alcoholic liver disease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69132-6
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DOI: https://doi.org/10.1038/s41467-026-69132-6
