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

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 TRAIPLSO mice exhibit heightened oxidative stress and inflammation but reduced steatosis, whereas TRAIPLKO 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.