OTULIN orchestrates NCOA4-FTH1 complex to alleviate APAP-induced hepatocyte Ferroptosis

Background: Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI) and can progress to acute liver failure (ALF). Hepatocyte death is widely recognized as the central event in APAP-induced liver injury; however, the underlying mechanisms are complex and not yet fully elucidated. Ferroptosis, a recently identified form of programmed cell death characterized by glutathione (GSH) depletion and disruption of cellular redox homeostasis, shares key features with APAP-induced hepatotoxicity. This study aimed to investigate the role of Ferroptosis in APAP-induced liver injury and to explore potential therapeutic targets.

Experimental approaches: C57BL/6 mice were administered APAP to evaluate Ferroptosis and hepatic injury in vivo through histological and biochemical analyses. A range of molecular techniques, along with the establishment of stable cell lines, were employed to elucidate the underlying mechanisms in vitro.

Results: We demonstrated that APAP disrupts iron homeostasis and promotes hepatocyte Ferroptosis. OTULIN, a Deubiquitinase involved in linear ubiquitination, was found to regulate the ubiquitination modification of NCOA4, leading to NCOA4 depletion and FTH1 accumulation. This process enhanced the resistance and adaptability of hepatocytes to APAP-induced damage.

Conclusion: Our findings reveal that OTULIN modulates the NCOA4-FTH1 complex to protect against APAP-induced hepatocyte Ferroptosis. Targeted upregulation of OTULIN in hepatocytes may represent a promising therapeutic strategy for APAP-induced DILI.

Acetaminophen; Drug-induced liver injury; Ferroptosis; NCOA4-FTH1 complex; OTULIN.