Research Article A Novel Antioxidant Multitarget Iron Chelator M30 Protects Hepatocytes against Ethanol-Induced Injury Jia Xiao, 1,2,3 Yi Lv, 2 Bin Lin, 3 George L. Tipoe, 3 Moussa B. H. Youdim, 4 Feiyue Xing, 2 and Yingxia Liu 1 1 National Key Disciplines for Infectious Diseases, Shenzhen hird People’s Hospital, Shenzhen 518112, China 2 Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, China 3 Department of Anatomy, he University of Hong Kong, Pokfulam, Hong Kong 4 Eve Topf Centers of Excellence, Technion, Rappaport Family Faculty of Medicine and Department of Pharmacology, 31096 Haifa, Israel Correspondence should be addressed to Feiyue Xing; tfyxing@jnu.edu.cn and Yingxia Liu; yingxialiu@hotmail.com Received 13 October 2014; Accepted 14 January 2015 Academic Editor: Vittorio Calabrese Copyright © 2015 Jia Xiao et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. he 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 efects 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 inlammation were examined. Speciic antagonists and agonists were applied to determine the involvements of hypoxia inducible factor-1 alpha (HIF-1) and its upstream adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA)/HIF-1/NOD-like receptor 3 (NLRP3) inlammasome pathway. We found that M30 signiicantly attenuated ethanol-induced cellular death, apoptosis, production of reactive oxygen species (ROS), and secretion of inlammatory cytokines and inhibited activation of the AC/cAMP/PKA/HIF-1/NLRP3 inlammasome pathway. Inhibition and activation of the AC/cAMP/PKA/HIF-1 pathway mimicked and abolished the efects of M30, respectively. In conclusion, inhibition of the AC/cAMP/PKA/HIF-1/NLRP3 inlammasome pathway by M30 partially contributes to its attenuation of hepatocyte injury caused by ethanol exposure. 1. Introduction Alcoholic liver diseases (ALDs), including acute alcoholic liver injury, liver failure, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH), annually result in an estimated 2.5 million deaths (4% of all mortality) world- wide [1]. Alcoholism or alcohol use disorder is deined as overconsumption of ethanol (men > 30 g/day and women > 20 g/day) [2]. he only deinitive clinical treatment for ALD is liver transplantation. Abstinence is critical but usually cannot reverse advanced ALD. It should be accompanied by supportive therapy and nutritional management [3]. To date, although a spectrum of key signaling pathways and thera- peutic targets have been described in ALD, the interaction between oxidative stress and inlammation is considered to be a central event during the initiation and progression of ALD [4, 5]. Inlammasomes are a group of large caspase-1-activating protein complexes in response to the evocation of innate immunity and the production of proinlammatory cytokines, interleukin-1 (IL-1), and IL-18. Inlammasome activation has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis [6]. Inlam- masomes, particularly NOD-like receptor 3 (NLRP3) inlam- masome, are shown to be activated in a variety of acute and chronic liver diseases, including ALD [7]. Our previous study found that Lycium barbarum polysaccharide atten- uated ethanol-induced hepatocyte injury partially through regulating the thioredoxin-interacting protein- (TXNIP-) NLRP3 inlammasome pathway [7]. However, the upstream Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2015, Article ID 607271, 11 pages http://dx.doi.org/10.1155/2015/607271