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<p>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.</p>

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MG53 mediates skeletal muscle-liver cross-talk and enhances alcohol metabolism in alcoholic liver disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月13日

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  • Tingting Shu,
  • Xindi Zeng,
  • Jing Wang,
  • Haijing Jiang,
  • Yuting Wang,
  • Mingming Zhang,
  • Lintao Jiang,
  • Bo He,
  • Lingzhi Yang,
  • Ning Liu,
  • Ming Tang,
  • Yuanyang Jiang,
  • Linfei Zhang,
  • Ping Chen,
  • Jun Xie,
  • Dandong Fang,
  • Kyung Eun Lee,
  • Yuchen Chen,
  • Jongsoo Kim,
  • Rongning Liu,
  • Yujia Ye,
  • Yu Han,
  • Jianjie Ma,
  • Chunyu Zeng

摘要

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.