SRC-mediated phosphorylation of UBC9 regulates inflammatory and metabolic signaling in alcohol-associated liver disease

Alcohol-associated liver disease (ALD) remains a major public health challenge with limited treatment options. NF-κB-driven inflammation in Kupffer cells (KCs) plays a central role in ALD, but the upstream regulators remain poorly understood. Here, we identify the tyrosine kinase SRC as a key mediator of ALD. Chronic ethanol exposure activates SRC in KCs, which directly phosphorylates ubiquitin-conjugating enzyme 9 (UBC9), the only E2 SUMO enzyme, at tyrosine-68 (Y68). This modification enhances NF-κB signaling and increases proinflammatory cytokines (TNF-α, IL-6, and IL-1β). These cytokines then promote hepatic lipogenesis through SREBP1c- and CEBPβ-dependent induction of FASN and ACC. Inhibition of UBC9 phosphorylation by gene editing or SRC inhibitor reduces NF-κB-dependent inflammation and lessens ethanol-induced liver injury in mouse models. These findings uncover a previously unrecognized SRC-UBC9-NF-κB axis that drives inflammation in ALD and highlight it as a potential therapeutic target in liver disease.