{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:02:40Z","timestamp":1775278960391,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204478"],"award-info":[{"award-number":["82204478"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273988"],"award-info":[{"award-number":["82273988"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20221033"],"award-info":[{"award-number":["BK20221033"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2632024ZD08"],"award-info":[{"award-number":["2632024ZD08"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Special Funds for Talents of Xinjiang Medical University","award":["0103010211"],"award-info":[{"award-number":["0103010211"]}]},{"name":"the Third Batch of Tianchi Talent Introduction Plan of Xinjiang Uygur Autonomous Region","award":["030106062543"],"award-info":[{"award-number":["030106062543"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Alcoholic liver disease (ALD), secondary to chronic alcohol abuse, encompasses a spectrum of liver disorders that progress from steatosis and hepatitis to fibrosis, cirrhosis, and acute-on-chronic liver failure. It poses a considerable global health burden due to its elevated rates of associated morbidity and mortality. The rising prevalence of ALD, coupled with the lack of approved pharmacotherapies, presents considerable unmet clinical needs. In this study, long-chain acyl-CoA synthetase 4 (ACSL4) was identified as a pathogenic driver in the context of chronic alcohol consumption. Hepatocyte Acsl4 ablation mitigated key pathological manifestations in Gao-Binge model mice, as evidenced by reduced inflammatory cell infiltration and attenuated lipid accumulation. Mechanistically, ACSL4 inhibition augmented cellular antioxidant defence through elevating gamma-glutamylcysteine (\u03b3-GC) levels. In addition, \u03b3-GC bound to and suppressed the expression of protein tyrosine phosphatase type IVA member 1 (PTP4A1). Both genetic silencing and pharmacological inhibition of PTP4A1 attenuated the activation of the downstream MAPK-NF-\u03baB inflammatory cascade. Dronedarone, identified as a novel compound targeting ACSL4, demonstrated efficacy in ameliorating the progression of ALD. Overall, these findings elucidate a novel mechanism wherein ACSL4 modulates antioxidant responses via a small bioactive peptide, highlighting ACSL4 as a potential therapeutic target for ALD.<\/jats:p>","DOI":"10.3390\/antiox15040438","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T10:09:21Z","timestamp":1775038161000},"page":"438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic ACSL4 Loss Boosts Endogenous Gamma-Glutamylcysteine to Alleviate Alcoholic Liver Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Ran","family":"Duan","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-Wen","family":"Ding","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-Jing","family":"Duan","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: Pathogenesis and new therapeutic targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"652","DOI":"10.3350\/cmh.2020.0160","article-title":"Global and regional impacts of alcohol use on public health: Emphasis on alcohol policies","volume":"26","author":"Park","year":"2020","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1001\/jama.2021.7683","article-title":"Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Review","volume":"326","author":"Singal","year":"2021","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S61","DOI":"10.1111\/j.1440-1746.2006.04575.x","article-title":"Methionine adenosyltransferase and S-adenosylmethionine in alcoholic liver disease","volume":"21","author":"Lu","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0016-5085(78)90401-8","article-title":"Corticosteroid therapy of alcoholic hepatitis","volume":"75","author":"Maddrey","year":"1978","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1053\/gast.2000.20189","article-title":"Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial","volume":"119","author":"Akriviadis","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.jhep.2006.05.009","article-title":"Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model","volume":"45","author":"Ji","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/nm.3372","article-title":"Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin","volume":"19","author":"Fullerton","year":"2013","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1074\/jbc.M008791200","article-title":"The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver","volume":"276","author":"Galli","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1053\/j.gastro.2004.09.049","article-title":"The role of AMP-activated protein kinase in the action of ethanol in the liver","volume":"127","author":"You","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1194\/jlr.M013292","article-title":"Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells","volume":"52","author":"Golej","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.bbalip.2019.07.013","article-title":"Long-chain acyl-CoA synthetase 4 participates in the formation of highly unsaturated fatty acid-containing phospholipids in murine macrophages","volume":"1864","author":"Kuwata","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nchembio.2239","article-title":"ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition","volume":"13","author":"Doll","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/hep.32148","article-title":"Therapeutic targeting of hepatic ACSL4 ameliorates NASH in mice","volume":"75","author":"Duan","year":"2022","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.bbi.2021.01.003","article-title":"ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation","volume":"93","author":"Cui","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s41392-022-00917-z","article-title":"Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia\/reperfusion","volume":"7","author":"Tuo","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1038\/s41418-019-0299-4","article-title":"Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia\/reperfusion","volume":"26","author":"Li","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102262","DOI":"10.1016\/j.redox.2022.102262","article-title":"ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury","volume":"51","author":"Wang","year":"2022","journal-title":"Redox Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nprot.2013.032","article-title":"Mouse model of chronic and binge ethanol feeding (the NIAAA model)","volume":"8","author":"Bertola","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/978-1-0716-0704-6_15","article-title":"Mouse Model of Alcoholic Steatohepatitis","volume":"2164","author":"Bertola","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119328","DOI":"10.1016\/j.lfs.2021.119328","article-title":"A review on molecular mechanism of alcoholic liver disease","volume":"274","author":"Namachivayam","year":"2021","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0741-8329(02)00200-8","article-title":"Neutrophil-mediated tissue injury in alcoholic hepatitis","volume":"27","author":"Jaeschke","year":"2002","journal-title":"Alcohol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1194\/jlr.R119000547","article-title":"Alcohol effects on hepatic lipid metabolism","volume":"61","author":"Jeon","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00204-009-0432-0","article-title":"Role of oxidative stress in alcohol-induced liver injury","volume":"83","author":"Cederbaum","year":"2009","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104931","DOI":"10.1016\/j.neuint.2020.104931","article-title":"Supplementation with \u03b3-glutamylcysteine (\u03b3-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD","volume":"144","author":"Liu","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.cell.2004.05.018","article-title":"Protein tyrosine phosphatases in the human genome","volume":"117","author":"Alonso","year":"2004","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42316","DOI":"10.1074\/jbc.M111.286302","article-title":"PRL-1 protein promotes ERK1\/2 and RhoA protein activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTPase-activating protein","volume":"286","author":"Bai","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/onc.2008.409","article-title":"New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53","volume":"28","author":"Min","year":"2009","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaau9952","DOI":"10.1126\/science.aau9952","article-title":"Branch-restricted localization of phosphatase Prl-1 specifies axonal synaptogenesis domains","volume":"364","author":"Urwyler","year":"2019","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110088","DOI":"10.1016\/j.intimp.2023.110088","article-title":"Trans-cinnamaldehyde attenuates renal ischemia\/reperfusion injury through suppressing inflammation via JNK\/p38 MAPK signaling pathway","volume":"118","author":"Chen","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s13238-010-0019-9","article-title":"MAPK signaling in inflammation-associated cancer development","volume":"1","author":"Huang","year":"2010","journal-title":"Protein Cell"},{"key":"ref_32","first-page":"135","article-title":"The risks associated with alcohol use and alcoholism","volume":"34","author":"Rehm","year":"2011","journal-title":"Alcohol Res. Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.dld.2019.12.008","article-title":"Alcohol associated liver disease 2020: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF)","volume":"52","author":"Addolorato","year":"2020","journal-title":"Dig. Liver Dis."},{"key":"ref_34","first-page":"113","article-title":"Current Management of Alcoholic Hepatitis and Future Therapies","volume":"4","author":"Saberi","year":"2016","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s12072-014-9516-x","article-title":"New drug targets for alcoholic liver disease","volume":"8","author":"Xu","year":"2014","journal-title":"Hepatol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1016\/j.jceh.2022.05.004","article-title":"Pathogenesis of Alcohol-Associated Liver Disease","volume":"12","author":"Osna","year":"2022","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1002\/hep4.1333","article-title":"Adipose-Specific Lipin-1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice","volume":"3","author":"Zhou","year":"2019","journal-title":"Hepatol. Commun."},{"key":"ref_38","first-page":"88","article-title":"Sirtuin 1 signaling and alcoholic fatty liver disease","volume":"4","author":"You","year":"2015","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"109404","DOI":"10.1016\/j.jnutbio.2023.109404","article-title":"\u03b3-glutamylcysteine alleviates insulin resistance and hepatic steatosis by regulating adenylate cyclase and IGF-1R\/IRS1\/PI3K\/Akt signaling pathways","volume":"119","author":"Zhou","year":"2023","journal-title":"J. Nutr. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s00011-023-01691-6","article-title":"\u03b3-Glutamylcysteine rescues mice from TNBS-driven inflammatory bowel disease through regulating macrophages polarization","volume":"72","author":"Zhou","year":"2023","journal-title":"Inflamm. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"110019","DOI":"10.1016\/j.cbi.2022.110019","article-title":"\u03b3-Glutamylcysteine attenuates amyloid-\u03b2 oligomers-induced neuroinflammation in microglia via blocking NF-\u03baB signaling pathway","volume":"363","author":"Bi","year":"2022","journal-title":"Chem.-Biol. Interact."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrc1837","article-title":"Protein-tyrosine phosphatases and cancer","volume":"6","author":"Ostman","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s41467-017-01168-1","article-title":"PTP4A1 promotes TGF\u03b2 signaling and fibrosis in systemic sclerosis","volume":"8","author":"Sacchetti","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.1016\/j.jmb.2019.06.008","article-title":"The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis","volume":"431","author":"Duciel","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3886","DOI":"10.1111\/febs.14503","article-title":"Physiological and oncogenic roles of the PRL phosphatases","volume":"285","author":"Hardy","year":"2018","journal-title":"FEBS J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4513","DOI":"10.1074\/jbc.274.8.4513","article-title":"Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Egr-1 activation is an early event in liver regeneration","volume":"274","author":"Peng","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cell.2005.05.016","article-title":"Redox redux: Revisiting PTPs and the control of cell signaling","volume":"121","author":"Tonks","year":"2005","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1002\/1521-4141(2000)30:8<2412::AID-IMMU2412>3.0.CO;2-J","article-title":"Subcellular localization of intracellular protein tyrosine phosphatases in T cells","volume":"30","author":"Saxena","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"29043","DOI":"10.1074\/jbc.M703537200","article-title":"Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for PRL1-mediated cell growth and migration","volume":"282","author":"Sun","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.alcohol.2016.08.008","article-title":"Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice","volume":"58","author":"Baker","year":"2017","journal-title":"Alcohol"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/438\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:18:41Z","timestamp":1775276321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antiox15040438"],"URL":"https:\/\/doi.org\/10.3390\/antiox15040438","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}