亚慢性酒精暴露通过巨噬细胞介导的炎症和线粒体功能障碍，加剧对乙酰氨基酚诱导的急性肝损伤

Abstract

Alcohol use is a major coexposure in patients taking acetaminophen (APAP), yet how subchronic alcohol exposure reshapes hepatic vulnerability to APAP remains incompletely defined. In this study, we examined the effects of chronic alcohol intake on APAP‐induced liver injury in mice. Our results indicated that subchronic alcohol exposure significantly increased the mortality rate in APAP‐overdosed mice. Alcohol pretreatment also exacerbated APAP‐induced hepatic damage, as evidenced by elevated serum ALT and AST levels, enhanced inflammatory responses, and aggravated oxidative stress. Quantitative polymerase chain reaction (qPCR) analysis revealed that alcohol consumption suppressed mitochondrial biogenesis (MB)‐related genes, including Pgc-1α and transcription factor A, mitochondrial ( TFAM ). Notably, macrophage depletion via clodronate liposomes not only attenuated hepatocyte injury and inflammation induction but also restored the expression of MB/function‐related genes, including Pgc-1α , TFAM , and Opa1 . These findings suggest macrophage‐involved inflammatory amplification may aggravate APAP‐induced liver injury, at least in part, by impairing mitochondrial adaptive repair responses.