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

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.