Cocaine-derived hippuric acid activates mtDNA-STING signaling in alcoholic liver disease: Implications for alcohol and cocaine co-abuse

Abstract The simultaneous abuse of alcohol and cocaine synergistically worsens liver injury, but the underlying mechanisms of this interaction remain poorly understood. This study demonstrates that cocaine exposure alone promotes liver injury and inflammation in both marmosets and mice. Notably, co-administration of cocaine and ethanol in mice exacerbates liver damage compared to individual treatments. Metabolomic analysis identifies hippuric acid (HA), a metabolite of cocaine produced in hepatocytes, as the most abundant serum metabolite in cocaine-treated marmosets. Mechanistically, HA increases mitochondrial DNA leakage in hepatocytes, leading to enhanced proinflammatory factor production via STING signaling in Kupffer cells (KCs). In addition, conditioned media from cocaine-treated KCs induces hepatocyte necroptosis through alcohol-induced TNFR1 activation. Importantly, disrupting STING signaling in vivo alleviates alcohol- and cocaine–induced liver injury and inflammation. These findings propose the HA-STING-TNFR1 axis as a potential therapeutic target for alcohol- and cocaine-induced excessive liver damage.