TRAIP Mediates Alcohol‐Induced Liver Injury through Regulating β‐catenin Ubiquitin Degradation via Direct Interaction

ABSTRACT Oxidative stress is a critical driver in the pathogenesis of alcohol‐related liver disease (ALD), promoting hepatic inflammation and injury. This study investigates the role of tumor necrosis factor receptor‐associated factor interacting protein (TRAIP) in ALD. We utilize in vivo ALD models with liver‐specific TRAIP overexpression (LSO) or knockout (LKO) mice. Chromatin immunoprecipitation and luciferase reporter assays confirm NF‐κB1 binding to the TRAIP promoter. In vitro, co‐immunoprecipitation and domain mapping with truncated mutants identify the interaction between the TRAIP coiled‐coil domain and the β‐catenin Armadillo domain. TRAIP is significantly upregulated in human and murine ALD tissues. Ethanol‐fed TRAIP LSO mice exhibit heightened oxidative stress and inflammation but reduced steatosis, whereas TRAIP LKO mice show the opposite. Mechanistically, ethanol‐induced NF‐κB1 activation transcriptionally upregulates TRAIP. TRAIP directly ubiquitinates β‐catenin in vitro and promotes its K48‐linked ubiquitination and proteasomal degradation in cells, independently of the canonical GSK3β/β‐TrCP pathway. Consequently, increased TRAIP suppresses the antioxidative response downstream of β‐catenin. The β‐catenin stabilizer SKL2001 effectively alleviates ethanol‐induced oxidative damage. We conclude that TRAIP promotes ALD by driving β‐catenin degradation and oxidative stress through a GSK3β/β‐TrCP‐independent mechanism, identifying the β‐catenin pathway and the compound SKL2001 as implicated in this process.