Loss of Ninjurin1 alleviates acetaminophen-induced liver injury via enhancing AMPKα-NRF2 pathway

Abstract

Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.

Keywords: AMPKα; Acetaminophen; Hepatocytes; NRF2; Nerve injury-induced protein 1 (Ninj1).