C/EBP homologous protein protects against acetaminophen-induced liver injury and promotes a FOS-associated antioxidant program

Acetaminophen (APAP) overdose is a major cause of acute liver injury that is primarily driven by oxidative stress and mitochondrial dysfunction resulting from excessive N-acetyl-p-benzoquinone imine formation. Although the transcription factor C/EBP homologous protein (CHOP) is markedly increased during APAP-induced liver injury (AILI), its functional role in hepatocellular stress responses remains unclear. In this study, we examined the role of CHOP in hepatic redox regulation during AILI and its relationship with Fos . Using wild-type and Chop -null mice, we found that CHOP deficiency significantly exacerbated AILI with elevated serum alanine aminotransferase levels and extensive necrosis. At the molecular level, CHOP deficiency led to impaired GSH-dependent antioxidant pathway induction and decreased hepatic reduced glutathione (GSH). Notably, APAP-induced Fos expression was strongly CHOP-dependent, and CHOP and FOS showed partial spatial overlap at the boundary between injured and preserved liver parenchyma. Promoter-reporter analysis and ChIP-qPCR further supported CHOP-dependent transcriptional regulation of Fos . These findings support a CHOP–FOS-associated antioxidant response that contributes to hepatic redox homeostasis by promoting GSH-dependent antioxidant defenses, thereby supporting hepatocyte adaptation during AILI.