Tingting Shu, Xindi Zeng, Jing Wang, H Jiang, Y. Wang, Mingming Zhang, Lintao Jiang, Bo He, Lingzhi Yang, Ning Liu, Ming Tang, Yuanyang Jiang, Linfei Zhang, P Chen, Jun Xie, Dandong Fang, Kyung Eun Lee, Yuchen Chen, Jongsoo Kim, Rongning Liu, Yujia Ye, Yu Han, Jianjie Ma, Chunyu Zeng
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. It was previously shown that Zinc deficiently worsens alcoholic liver disease. This study identified muscle-derived MG53 is transported to liver and mitigates liver damage through alcohol dehydrogenase and aldehyde dehydrogenase