Stress protein CHOP shields the liver from acetaminophen damage, mouse study finds

The protein, C/EBP homologous protein (CHOP), was found to defend the liver against injury by promoting a glutathione-dependent antioxidant program that operates through the FOS protein.

Acetaminophen overdose is a major cause of acute liver injury. The damage is driven primarily by oxidative stress and mitochondrial dysfunction that result from excessive formation of N-acetyl-p-benzoquinone imine, a reactive metabolite of the drug. Although CHOP levels rise markedly during acetaminophen-induced liver injury, its functional role in hepatocellular stress responses had remained unclear.

To probe that role, the research team compared wild-type mice with mice lacking the Chop gene. When both groups received acetaminophen, the absence of CHOP significantly worsened the liver injury. The Chop-null animals showed elevated serum alanine aminotransferase levels, a standard marker of liver damage, along with extensive necrosis of liver tissue.

The molecular explanation pointed to a weakened antioxidant defense. CHOP deficiency impaired the induction of GSH-dependent antioxidant pathways and reduced the hepatic levels of reduced glutathione, the molecule that normally buffers the oxidative assault triggered by acetaminophen metabolism.

A striking finding was the dependence of Fos expression on CHOP. The acetaminophen-induced rise in Fos expression was strongly CHOP-dependent, suggesting that CHOP sits upstream of this antioxidant-linked transcriptional response rather than acting in a parallel pathway.

Spatial analysis added a further layer of detail. CHOP and FOS showed partial overlap in their distribution at the boundary between injured and preserved liver parenchyma, the region where surviving hepatocytes are mounting their adaptive response to the toxic challenge.

Two independent lines of evidence supported the regulatory link. Promoter-reporter analysis and ChIP-qPCR both supported CHOP-dependent transcriptional regulation of the Fos gene.

The authors conclude that a CHOP–FOS-associated antioxidant response contributes to hepatic redox homeostasis by promoting GSH-dependent antioxidant defenses, thereby supporting hepatocyte adaptation during acetaminophen-induced liver injury. The work was performed in mice, so direct implications for human patients with acetaminophen poisoning will require further investigation. The article was published as peer-reviewed accepted research on 23 October 2026, with a final version of record to follow.

Subject of Research: The role of the transcription factor CHOP in protecting the liver from acetaminophen-induced injury through a FOS-associated antioxidant program in mice.

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

Article References: Nguyen, V. D., Daikoku, A., Ando, M., Kosugi, M., Kadono, C., Nakai, H., Yuasa, H., Urushima, H., Gi, M., Kawamura, E., Gonzalez, F. J., & Matsubara, T. (2026). C/EBP homologous protein protects against acetaminophen-induced liver injury and promotes a FOS-associated antioxidant program. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-026-10318-5

Image Credits: AI Generated

DOI: 10.1007/s10565-026-10318-5

Keywords: acetaminophen, liver injury, CHOP, FOS, glutathione, oxidative stress, hepatotoxicity, transcription factor, mouse study, antioxidant defense, homologous, protein