Zinc-dependent RNA-Binding Protein Controls Hepatocyte Senescence and Recovery from Alcohol-related Liver Failure

Why alcohol-induced liver disease (ALD) resolves after abstinence in most people but progresses to liver failure in others remains poorly understood. Experimental models show that increased exposure to pro-inflammatory cytokines exacerbates ALD, yet clinical trials targeting these cytokines have failed. The TNFα-inducible zinc finger protein 36 (ZFP 36) family of RNA binding proteins controls the outcomes of TNFα exposure by destabilizing suites of mRNAs that execute the pleiotropic downstream actions of TNFα. To investigate the role of RNA binding protein ZFP36L1 in regulating hepatocyte fate and its contribution in the progression of ALD.We selectively deleted ZFP36L1 in mouse hepatocytes (ZFP36L1HEPKO) to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analyzed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity, and zinc-dependent regulation.Deletion of ZFP36L1 exacerbated ALD and activated transcriptional programs driving ductal trans-differentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilized Cdkn1a (p21) and Jag1 mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signaling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity, and was closely associated with impaired zinc-dependent signaling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets. These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation, and highlight ZFP36L1as a promising therapeutic target in ALD.