Zinc-dependent RNA-binding protein controls hepatocyte senescence and recovery from alcohol-related liver failure

BACKGROUND: Why alcohol-associated 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 proinflammatory cytokines exacerbates ALD, yet clinical trials targeting these cytokines have failed. The tumour necrosis factor alpha (TNFα)-inducible zinc finger protein 36 (ZFP 36) family of RNA binding proteins controls the outcomes of TNFα exposure by destabilising suites of messenger RNAs (mRNAs) that execute the pleiotropic downstream actions of TNFα. OBJECTIVE: To investigate the role of RNA binding protein ZFP36 ring finger protein like 1 (ZFP36L1) in regulating hepatocyte fate and its contribution to the progression of ALD. DESIGN: We selectively deleted ZFP36L1 in mouse hepatocytes to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analysed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity and zinc-dependent regulation. RESULTS: Deletion of ZFP36L1 exacerbated experimental ALD and activated transcriptional programmes driving ductal transdifferentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilised cyclin-dependent kinase inhibitor 1A (Cdkn1a)(p21) and jagged canonical notch ligand 1 (Jag1) mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signalling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity and was closely associated with impaired zinc-dependent signalling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets. CONCLUSION: These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation and highlight ZFP36L1 as a promising therapeutic target in ALD.