College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, 28160, South Korea.
Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Cell Biol Toxicol. 2024 Aug 16;40(1):71. doi: 10.1007/s10565-024-09901-5.
The simultaneous abuse of alcohol-cocaine is known to cause stronger and more unpredictable cellular damage in the liver, heart, and brain. However, the mechanistic crosstalk between cocaine and alcohol in liver injury remains unclear. The findings revealed cocaine-induced liver injury and inflammation in both marmosets and mice. Of note, co-administration of cocaine and ethanol in mice causes more severe liver damage than individual treatment. The metabolomic analysis confirmed that hippuric acid (HA) is the most abundant metabolite in marmoset serum after cocaine consumption and that is formed in primary marmoset hepatocytes. HA, a metabolite of cocaine, increases mitochondrial DNA leakage and subsequently increases the production of proinflammatory factors via STING signaling in Kupffer cells (KCs). In addition, conditioned media of cocaine-treated KC induced hepatocellular necrosis via alcohol-induced TNFR1. Finally, disruption of STING signaling in vivo ameliorated co-administration of alcohol- and cocaine-induced liver damage and inflammation. These findings postulate intervention of HA-STING-TNFR1 axis as a novel strategy for treatment of alcohol- and cocaine-induced excessive liver damage.
同时滥用酒精和可卡因已知会导致肝脏、心脏和大脑中的细胞损伤更强烈和更不可预测。然而,可卡因和酒精在肝损伤中的机制相互作用仍不清楚。研究结果显示,可卡因在狨猴和小鼠中均可引起肝损伤和炎症。值得注意的是,可卡因和乙醇在小鼠中的联合给药比单独治疗引起更严重的肝损伤。代谢组学分析证实,在摄入可卡因后,马氏猕猴血清中含量最丰富的代谢物是马尿酸(HA),并且在原代马氏猕猴肝细胞中形成。可卡因的代谢物 HA 会增加线粒体 DNA 渗漏,随后通过 Kupffer 细胞 (KC) 中的 STING 信号增加促炎因子的产生。此外,经可卡因处理的 KC 的条件培养基通过酒精诱导的 TNFR1 诱导肝细胞坏死。最后,体内破坏 STING 信号可改善酒精和可卡因联合给药引起的肝损伤和炎症。这些发现提出了干预 HA-STING-TNFR1 轴作为治疗酒精和可卡因引起的过度肝损伤的新策略。