A Novel Antioxidant Multitarget Iron Chelator M30 Protects Hepatocytes against Ethanol-Induced Injury

The multitarget iron chelator, M30, is a novel antioxidant and protective agent against oxidative stress in a spectrum of diseases. However, there is no report regarding its role in liver diseases. Since oxidative stress is one of the major pathological events during the progression of alcoholic liver diseases, the protective effects and mechanisms of M30 on ethanol-induced hepatocyte injury were investigated in this study. Rat hepatocyte line BRL-3A was pretreated with M30 prior to ethanol treatment. Cell death, apoptosis, oxidative stress, and inflammation were examined. Specific antagonists and agonists were applied to determine the involvements of hypoxia inducible factor-1 alpha (HIF-1α) and its upstream adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA)/HIF-1α/NOD-like receptor 3 (NLRP3) inflammasome pathway. We found that M30 significantly attenuated ethanol-induced cellular death, apoptosis, production of reactive oxygen species (ROS), and secretion of inflammatory cytokines and inhibited activation of the AC/cAMP/PKA/HIF-1α/NLRP3 inflammasome pathway. Inhibition and activation of the AC/cAMP/PKA/HIF-1α pathway mimicked and abolished the effects of M30, respectively. In conclusion, inhibition of the AC/cAMP/PKA/HIF-1α/NLRP3 inflammasome pathway by M30 partially contributes to its attenuation of hepatocyte injury caused by ethanol exposure.