{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:59:16Z","timestamp":1789721956083,"version":"4.0.1"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangxi Natural Science Foundation Joint Special Project","award":["2024JJH130036"],"award-info":[{"award-number":["2024JJH130036"]}]},{"DOI":"10.13039\/501100004761","name":"Natural Science Foundation of Hunan Province of China","doi-asserted-by":"crossref","award":["2023JJ50440"],"award-info":[{"award-number":["2023JJ50440"]}],"id":[{"id":"10.13039\/501100004761","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Drug-induced liver injury remains a significant challenge in both drug development and clinical applications. Acetaminophen (APAP), a commonly used analgesic and antipyretic, can cause liver damage when overdosed, with APAP-induced liver injury being one of the leading causes of acute liver injury.\n                      <jats:italic>Kummerowia striata<\/jats:italic>\n                      (Ks), a leguminous plant, has been reported to contain chemical compounds with anti-inflammatory and antioxidant activities. However, its potential therapeutic effects in liver diseases remain inadequately explored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This study aims to investigate the protective effect of\n                      <jats:italic>\n                        <jats:italic>Kummerowia striata<\/jats:italic>\n                      <\/jats:italic>\n                      extract against APAP-induced acute liver injury and further explore its potential molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>C57BL\/6J mice were pre-treated with Ks extract by gavage for 3 days. On the second day, treatment was discontinued, and the mice were fasted for 16 hours. After the fasting period, the final dose of Ks extract was administered, followed by an intraperitoneal injection of APAP (300 mg\/kg) 1 hour later to establish a drug-induced liver injury model. Tissue samples were collected 24 hours after modeling. To investigate the molecular mechanisms by which Ks extract prevents APAP-induced acute liver injury, network pharmacology, the GEO database, and molecular docking analysis were employed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ks extract exhibited a significant gender-independent protective effect in preventing APAP-induced acute liver injury in mice. In male mice, Ks extract attenuated the occurrence of acute liver injury by modulating the sphingosine-1-phosphate\/ Sphingosine-1-Phosphate Receptor 2\/ Sphingosine-1-Phosphate Receptor 4(S1P\/S1PR2\/S1PR4) signaling pathway and the upstream regulator SPHK1. This, in turn, regulated the binding of Kelch Like ECH Associated Protein 1 (Keap1) to Nuclear factor erythroid 2-related factor 2(Nrf2), alleviating oxidative stress and inflammatory responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec005\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study illustrates that Ks exerts a protective effect against APAP-induced acute liver injury by modulating oxidative stress and inflammatory responses through multiple mechanisms. Notably, Ks inhibited Keap1 expression and restored Nrf2 signaling, indicating a potential regulatory role in mitigating mitochondrial oxidative damage and ferroptosis. Furthermore, Ks downregulated SPHK1 expression and reduced levels of the bioactive sphingolipid S1P, as well as its receptors S1PR2 and S1PR4, unveiling a previously unreported involvement of the SPHK1\/S1P\/S1PR2\/4 axis in liver injury. Interestingly, sex-based differences in APAP hepatotoxicity were observed, with female mice exhibiting lower susceptibility, yet still responding to Ks treatment. These findings not only validate the hepatoprotective potential of Ks but also provide new mechanistic insights involving the Nrf2\/Keap1 and S1P\/S1PR2\/S1PR4 signaling pathways, thereby laying a foundation for its development as a candidate therapeutic agent for acute liver injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0329837","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T18:12:02Z","timestamp":1755195122000},"page":"e0329837","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Kummerowia striata extract protects paracetamol-induced liver injury by modulating the S1P\/Nrf2\/Keap1 pathway"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8693-4010","authenticated-orcid":true,"given":"Huanghui","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runxiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youlan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6862-0677","authenticated-orcid":true,"given":"Hang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8548-9615","authenticated-orcid":true,"given":"Lanyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"issue":"9","key":"pone.0329837.ref001","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1111\/liv.15262","article-title":"Incidence and risk factors of drug-induced liver injury","volume":"42","author":"X Li","year":"2022","journal-title":"Liver Int"},{"key":"pone.0329837.ref002","doi-asserted-by":"crossref","first-page":"17562848231163410","DOI":"10.1177\/17562848231163410","article-title":"Drug-induced liver injury: a comprehensive review","volume":"16","author":"T Hosack","year":"2023","journal-title":"Therap Adv Gastroenterol"},{"issue":"6","key":"pone.0329837.ref003","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.jhep.2017.07.005","article-title":"Acetaminophen (APAP) hepatotoxicity\u2014isn\u2019t it time for APAP to go away?","volume":"67","author":"WM Lee","year":"2017","journal-title":"Journal of Hepatology"},{"issue":"10","key":"pone.0329837.ref004","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1007\/s00204-021-03142-9","article-title":"Delayed administration of N-acetylcysteine blunts recovery after an acetaminophen overdose unlike 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Bu","year":"2021","journal-title":"Front Pharmacol"},{"issue":"13","key":"pone.0329837.ref019","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.3390\/cells11132058","article-title":"Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway Modulators, from Current Insights to Future Perspectives","volume":"11","author":"G\u00c1 Bravo","year":"2022","journal-title":"Cells"},{"key":"pone.0329837.ref020","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.freeradbiomed.2020.03.023","article-title":"Beyond repression of Nrf2: An update on Keap1","volume":"157","author":"A Kopacz","year":"2020","journal-title":"Free Radical Biology & Medicine"},{"issue":"13","key":"pone.0329837.ref021","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.3390\/ijms21134777","article-title":"NRF2, a Transcription Factor for Stress Response and Beyond","volume":"21","author":"F He","year":"2020","journal-title":"Int J Mol 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Mice","volume":"2018","author":"L Xu","year":"2018","journal-title":"Oxid Med Cell Longev"},{"issue":"4","key":"pone.0329837.ref025","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1097\/HEP.0000000000000367","article-title":"Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury","volume":"78","author":"M Kotulkar","year":"2023","journal-title":"Hepatology"},{"key":"pone.0329837.ref026","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1091","article-title":"Updated resources for exploring experimentally-determined PDB structures and Computed Structure Models at the RCSB Protein Data Bank","volume":"53","author":"SK Burley","year":"2025","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"pone.0329837.ref027","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"issue":"2","key":"pone.0329837.ref028","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/hep.31209","article-title":"Decreased Hepatocyte Autophagy Leads to Synergistic IL-1\u03b2 and TNF Mouse Liver Injury and Inflammation","volume":"72","author":"Y Shen","year":"2020","journal-title":"Hepatology"},{"key":"pone.0329837.ref029","doi-asserted-by":"crossref","first-page":"105510","DOI":"10.1016\/j.antiviral.2022.105510","article-title":"MicroRNA-124 expression in Kupffer cells modulates liver injury by targeting IL-6\/STAT3 signaling","volume":"211","author":"J Wang","year":"2023","journal-title":"Antiviral Res"},{"issue":"8004","key":"pone.0329837.ref030","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/s41586-024-07098-5","article-title":"IL-10 constrains sphingolipid metabolism to limit inflammation","volume":"627","author":"AG York","year":"2024","journal-title":"Nature"},{"issue":"18","key":"pone.0329837.ref031","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1111\/febs.16336","article-title":"Nrf2 and oxidative stress in liver ischemia\/reperfusion injury","volume":"289","author":"R G Bardallo","year":"2022","journal-title":"FEBS J"},{"key":"pone.0329837.ref032","doi-asserted-by":"crossref","first-page":"112533","DOI":"10.1016\/j.intimp.2024.112533","article-title":"Icaritin attenuates ischemia-reperfusion injury by anti-inflammation, anti-oxidative stress, and anti-autophagy in mouse liver","volume":"138","author":"Q Sun","year":"2024","journal-title":"Int Immunopharmacol"},{"issue":"11","key":"pone.0329837.ref033","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.3390\/nu9111180","article-title":"Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation","volume":"9","author":"GH Norris","year":"2017","journal-title":"Nutrients"},{"issue":"2","key":"pone.0329837.ref034","doi-asserted-by":"crossref","first-page":"73","DOI":"10.21037\/atm-22-6460","article-title":"Hydrogen sulfide alleviates ischemia induced liver injury by repressing the SPHK1\/S1P pathway","volume":"11","author":"L Chen","year":"2023","journal-title":"Ann Transl Med"},{"issue":"3","key":"pone.0329837.ref035","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/hep.31321","article-title":"Inhibition of Sphingosine-1-Phosphate-Induced Th17 Cells Ameliorates Alcohol-Associated Steatohepatitis in Mice","volume":"73","author":"S Chu","year":"2021","journal-title":"Hepatology"},{"issue":"2","key":"pone.0329837.ref036","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00109-020-02032-4","article-title":"NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate\/S1P receptor 2\/G\u03b1(12\/13)\/MAPK signaling pathway","volume":"99","author":"L Hou","year":"2021","journal-title":"J Mol Med (Berl)"},{"key":"pone.0329837.ref037","doi-asserted-by":"crossref","first-page":"1371461","DOI":"10.3389\/fmed.2024.1371461","article-title":"Advantages of Chinese herbal medicine in treating rheumatoid arthritis: a focus on its anti-inflammatory and anti-oxidative effects","volume":"11","author":"X Wang","year":"2024","journal-title":"Front Med (Lausanne)"},{"issue":"4","key":"pone.0329837.ref038","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.apsb.2019.02.006","article-title":"Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway","volume":"9","author":"Y Liu","year":"2019","journal-title":"Acta Pharm Sin B"},{"issue":"4","key":"pone.0329837.ref039","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s12325-020-01251-y","article-title":"Silymarin as Supportive Treatment in Liver 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Wang","year":"2021","journal-title":"Chinese Prescription Drugs"},{"issue":"1","key":"pone.0329837.ref043","doi-asserted-by":"crossref","first-page":"3648","DOI":"10.1038\/s41467-023-39412-6","article-title":"USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice","volume":"14","author":"C Cai","year":"2023","journal-title":"Nat Commun"},{"key":"pone.0329837.ref044","doi-asserted-by":"crossref","first-page":"124775","DOI":"10.1016\/j.jenvman.2025.124775","article-title":"Decabromodiphenyl ethane exposure-mediated mitochondrial dysfunction drives oxeiptosis in placental trophoblasts and induces fetal growth restriction","volume":"379","author":"L Xie","year":"2025","journal-title":"J Environ Manage"},{"key":"pone.0329837.ref045","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.coi.2018.10.006","article-title":"Oxeiptosis: a discreet way to respond to radicals","volume":"56","author":"P 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