Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Toxicant-induced liver injury necessitates the identification of targets and therapeutic agents. Gα12 signaling axis has been implicated in cell viability. This study aims to explore the role of the Gα12 signaling axis in endoplasmic reticulum (ER) stress-induced ferroptosis by toxicant, and the effect of NEMO as a cell-survival component in this process. Gα12 overexpression in hepatocytes increased toxicity, promoting lipid peroxidation, inflammation, and ferroptosis. IRE1α-dependent Xbp1 transactivated Gna12, facilitating Gα12 overerexpression. In this event, the level of miR-15a, identified as an ALOX12 inhibitor, was decreased. Thus, Gα12 overexpression by ER stress contributes to hepatocyte ferroptosis through ROCK1-mediated dysregulation of ALOX12. In an effort to find a cell-survival component that acts against ferroptosis in association with Gα12, we next focused on NF-κB essential modulator (NEMO), a protein known as a regulator of inflammation and cell death. Nrf2 transcriptionally induced NEMO. Hepatocyte-specific overexpression of Gα12 inhibited NEMO in mice. Conversely, Gα12 deficiency prevented toxicant from inhibiting NEMO, suggesting post-transcriptional control. Moreover, decrease of Gα12 lowered miR-125a, a novel inhibitor of NEMO. The significance of Gα12 in NEMO-dependent hepatocyte survival was confirmed via ROCK1. These results were validated in human specimens. Together, our results show that Gα12 overexpression by toxicant-induced ER stress causes ferroptosis in the liver through ALOX12, which can be overcome by Nrf2-dependent NEMO induction. Our findings may provide ways to ameliorate toxicant-induced hepatic injury.
