{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T17:41:13Z","timestamp":1791740473517,"version":"4.3.4"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Acetaminophen (APAP) is widely used as an analgesic and antipyretic. However overdose APAP can lead to acute liver injury (ALI), representing a significant challenge for public health due to limited treatment options. Current research highlights the need for safer and more effective therapies for APAP-induced liver injury, especially those that target oxidative and endoplasmic reticulum (ER) stress pathways. This study investigates the protective effects of Thonningianin A (TA), a flavonoid compound derived from <jats:italic>Penthorum chinense Pursh<\/jats:italic>, in mitigating APAP-induced hepatotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The experimental design involved administering TA at doses of 20\u00a0mg\/kg and 40\u00a0mg\/kg to C57BL\/6 mice prior to inducing hepatotoxicity with APAP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>TA treatment significantly lowered plasma ALT and AST levels, inhibited the production of inflammatory cytokines, and reduced oxidative stress markers in liver tissues. Furthermore, TA modulated apoptosis-related proteins by increasing BCL-2 expression while decreasing CHOP and BAX levels. It alleviated endoplasmic reticulum (ER) stress by downregulating GRP78, p-PERK, and ATF4. Notably, liver-specific GPX4 knockdown, achieved through AAV-8-mediated shRNA delivery, abolished the hepatoprotective effects of TA, underscoring GPX4\u2019s essential role in mediating TA-induced hepatoprotection. These findings suggest TA as a promising therapeutic agent in managing APAP-induced liver injury, with its unique action on both oxidative and ER stress pathways contributing to its hepatoprotective efficacy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1531277","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T06:42:01Z","timestamp":1740033721000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Thonningianin A ameliorates acetaminophen-induced liver injury by activating GPX4 and modulating endoplasmic reticulum stress"],"prefix":"10.3389","volume":"16","author":[{"given":"Shanglei","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyan","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinchao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokai","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchen","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1002\/hep.32562","article-title":"Endoplasmic reticulum stress in liver diseases","volume":"77","author":"Ajoolabady","year":"2023","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"341","DOI":"10.2174\/187152011795677544","article-title":"Superoxide dismutase in redox biology: the roles of superoxide and hydrogen peroxide","volume":"11","author":"Buettner","year":"2011","journal-title":"Anticancer Agents Med. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1631\/jzus.B2100977","article-title":"Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options","volume":"23","author":"Cai","year":"2022","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"B4","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1124\/dmd.121.000732","article-title":"Novel clinical biomarkers for drug-induced liver injury","volume":"50","author":"Chen","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"B5","doi-asserted-by":"publisher","first-page":"13905","DOI":"10.1096\/fj.201901258RR","article-title":"Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression","volume":"33","author":"Chen","year":"2019","journal-title":"FASEB J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"7906091","DOI":"10.1155\/2022\/7906091","article-title":"Reactive oxygen species and oxidative stress in vascular-related diseases","volume":"2022","author":"Cheng","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"154510","DOI":"10.1016\/j.phymed.2022.154510","article-title":"Acetaminophen induced hepatotoxicity: an overview of the promising protective effects of natural products and herbal formulations","volume":"108","author":"Chilvery","year":"2023","journal-title":"Phytomedicine"},{"key":"B8","doi-asserted-by":"publisher","first-page":"105102","DOI":"10.1016\/j.phrs.2020.105102","article-title":"Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity","volume":"161","author":"Chowdhury","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s00726-011-0867-5","article-title":"The oxidative stress-inducible cystine\/glutamate antiporter, system x (c) (-): cystine supplier and beyond","volume":"42","author":"Conrad","year":"2012","journal-title":"Amino Acids"},{"key":"B10","doi-asserted-by":"publisher","first-page":"111259","DOI":"10.1016\/j.foodres.2022.111259","article-title":"Lactobacillus plantarum ZY08 relieves chronic alcohol-induced hepatic steatosis and liver injury in mice via restoring intestinal flora homeostasis","volume":"157","author":"Ding","year":"2022","journal-title":"Food Res. Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","article-title":"Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential","volume":"10","author":"Du","year":"2016","journal-title":"Redox Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7925","DOI":"10.1039\/d0fo00724b","article-title":"Kaempferol from Penthorum chinense Pursh suppresses HMGB1\/TLR4\/NF-\u03baB signaling and NLRP3 inflammasome activation in acetaminophen-induced hepatotoxicity","volume":"11","author":"Du","year":"2020","journal-title":"Food Funct."},{"key":"B13","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.jhep.2021.06.021","article-title":"Advanced preclinical models for evaluation of drug-induced liver injury\u2013consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]","volume":"75","author":"Fernandez-Checa","year":"2021","journal-title":"J. Hepatol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e1800311","DOI":"10.1002\/pmic.201800311","article-title":"GPX4 at the crossroads of lipid homeostasis and ferroptosis","volume":"19","author":"Forcina","year":"2019","journal-title":"Proteomics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"628","DOI":"10.3390\/antiox12030628","article-title":"Rosemary (rosmarinus officinalis L.) glycolic extract protects liver mitochondria from oxidative damage and prevents acetaminophen-induced hepatotoxicity","volume":"12","author":"Guimaraes","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"221","DOI":"10.31083\/j.fbl2906221","article-title":"Crosstalk between endoplasmic reticulum stress and ferroptosis in liver diseases","volume":"29","author":"Huang","year":"2024","journal-title":"Front. Biosci. Landmark Ed."},{"key":"B17","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/82_2016_508","article-title":"Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis","volume":"403","author":"Imai","year":"2017","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3390\/biology10050399","article-title":"Cell death via lipid peroxidation and protein aggregation diseases","volume":"10","author":"Iuchi","year":"2021","journal-title":"Biology (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1016\/j.apsb.2021.09.023","article-title":"Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls","volume":"11","author":"Jaeschke","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"B20","doi-asserted-by":"publisher","first-page":"102412","DOI":"10.1016\/j.redox.2022.102412","article-title":"Emerging roles of ER-resident selenoproteins in brain physiology and physiopathology","volume":"55","author":"Jehan","year":"2022","journal-title":"Redox Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"22","DOI":"10.4103\/jcrt.JCRT_862_16","article-title":"Oxidative stress and its role in cancer","volume":"17","author":"Jelic","year":"2021","journal-title":"J. Cancer Res. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1007\/s00535-016-1256-3","article-title":"Sodium 4-phenylbutyric acid prevents murine acetaminophen hepatotoxicity by minimizing endoplasmic reticulum stress","volume":"52","author":"Kusama","year":"2017","journal-title":"J. Gastroenterol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/s10495-020-01642-0","article-title":"The interplay between apoptosis and ferroptosis mediated by ER stress","volume":"25","author":"Lee","year":"2020","journal-title":"Apoptosis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s12033-024-01148-z","article-title":"Role of C\/EBP homologous protein (CHOP) and Nupr1 interaction in endoplasmic reticulum stress-induced apoptosis of lens epithelial cells","author":"Li","year":"2024","journal-title":"Mol. Biotechnol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1038\/s41418-019-0471-x","article-title":"SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition","volume":"27","author":"Li","year":"2020","journal-title":"Cell. Death Differ."},{"key":"B26","doi-asserted-by":"publisher","first-page":"118107","DOI":"10.1016\/j.jep.2024.118107","article-title":"Paeonia lactiflora Pall. ameliorates acetaminophen-induced oxidative stress and apoptosis via inhibiting the PKC-ERK pathway","volume":"329","author":"Li","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1122632","DOI":"10.3389\/fphar.2023.1122632","article-title":"Acetaminophen-induced liver injury: molecular mechanism and treatments from natural products","volume":"14","author":"Liao","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"11097","DOI":"10.1021\/jf303755w","article-title":"Isolation and identification of compounds from Penthorum chinense Pursh with antioxidant and antihepatocarcinoma properties","volume":"60","author":"Lu","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10565-024-09842-z","article-title":"ARRB1 downregulates acetaminophen-induced hepatoxicity through binding to p-eIF2\u03b1 to inhibit ER stress signaling","volume":"40","author":"Luo","year":"2024","journal-title":"Cell. Biol. Toxicol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1124\/dmd.123.001280","article-title":"Good cells go bad: immune dysregulation in the transition from acute liver injury to liver failure after acetaminophen overdose","volume":"52","author":"Luyendyk","year":"2024","journal-title":"Drug Metab. Dispos."},{"key":"B31","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1089\/ars.2017.7115","article-title":"GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues","volume":"29","author":"Maiorino","year":"2018","journal-title":"Antioxid. Redox Signal"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1042\/BST20220682","article-title":"GPX4: old lessons, new features","volume":"50","author":"Nishida Xavier da Silva","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1147414","DOI":"10.3389\/fphar.2023.1147414","article-title":"Research progress of glutathione peroxidase family (GPX) in redoxidation","volume":"14","author":"Pei","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"940629","DOI":"10.3389\/fphar.2022.940629","article-title":"Melatonin promotes sirtuin 1 expression and inhibits IRE1\u03b1-XBP1S-CHOP to reduce endoplasmic reticulum stress-mediated apoptosis in chondrocytes","volume":"13","author":"Qin","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2174\/1566524016666160523143937","article-title":"The role of the PERK\/eIF2\u03b1\/ATF4\/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress","volume":"16","author":"Rozpedek","year":"2016","journal-title":"Curr. Mol. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"176084","DOI":"10.1016\/j.ejphar.2023.176084","article-title":"L-type calcium ion channel-mediated activation of autophagy in vascular smooth muscle cells via thonningianin A (TA) alleviates vascular calcification in type 2 diabetes mellitus","volume":"959","author":"Shen","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"752","DOI":"10.7150\/ijbs.40612","article-title":"Hepatoprotective effect of citrus aurantium L. Against APAP-induced liver injury by regulating liver lipid metabolism and apoptosis","volume":"16","author":"Shu","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.freeradbiomed.2019.10.417","article-title":"The active components derived from Penthorum chinensePursh protect against oxidative-stress-induced vascular injury via autophagy induction","volume":"146","author":"Sun","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"7885","DOI":"10.1039\/d2fo00357k","article-title":"Activation of Atg7-dependent autophagy by a novel inhibitor of the Keap1-Nrf2 protein-protein interaction from Penthorum chinense Pursh. attenuates 6-hydroxydopamine-induced ferroptosis in zebrafish and dopaminergic neurons","volume":"13","author":"Sun","year":"2022","journal-title":"Food Funct."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2925","DOI":"10.1007\/s00204-020-02780-9","article-title":"Autophagy: a promising process for the treatment of acetaminophen-induced liver injury","volume":"94","author":"Tan","year":"2020","journal-title":"Arch. Toxicol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"870239","DOI":"10.3389\/fimmu.2022.870239","article-title":"Reactive oxygen species induce fatty liver and ischemia-reperfusion injury by promoting inflammation and cell death","volume":"13","author":"Tang","year":"2022","journal-title":"Front. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2020.02.027","article-title":"Lipid peroxidation and ferroptosis: the role of GSH and GPx4","volume":"152","author":"Ursini","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1002\/mc.23437","article-title":"Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)","volume":"61","author":"van der Mijn","year":"2022","journal-title":"Mol. Carcinog."},{"key":"B44","doi-asserted-by":"publisher","first-page":"106435","DOI":"10.1016\/j.intimp.2020.106435","article-title":"Hesperetin attenuated acetaminophen-induced hepatotoxicity by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via upregulation of heme oxygenase-1 expression","volume":"83","author":"Wan","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s00253-023-12996-1","article-title":"Activity of thonningianin A against Candida albicans in vitro and in vivo","volume":"108","author":"Wang","year":"2024","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1007\/s10753-020-01388-6","article-title":"Sappanone A protects against inflammation, oxidative stress and apoptosis in cerebral ischemia-reperfusion injury by alleviating endoplasmic reticulum stress","volume":"44","author":"Wang","year":"2021","journal-title":"Inflammation"},{"key":"B47","doi-asserted-by":"publisher","first-page":"112917","DOI":"10.1016\/j.biopha.2022.112917","article-title":"Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis","volume":"149","author":"Wang","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/j.molcel.2022.03.025","article-title":"Reshaping endoplasmic reticulum quality control through the unfolded protein response","volume":"82","author":"Wiseman","year":"2022","journal-title":"Mol. Cell."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1080\/15548627.2023.2218764","article-title":"GPX4 in cell death, autophagy, and disease","volume":"19","author":"Xie","year":"2023","journal-title":"Autophagy"},{"key":"B50","doi-asserted-by":"publisher","first-page":"115331","DOI":"10.1016\/j.ecoenv.2023.115331","article-title":"Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK\/SIRT1 pathway","volume":"262","author":"Xu","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B51","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/978-3-030-74180-8_3","article-title":"Amino acids in endoplasmic reticulum stress and redox signaling","volume":"1332","author":"Yang","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"6161","DOI":"10.7150\/thno.98172","article-title":"A novel ferroptosis inhibitor, Thonningianin A, improves Alzheimer\u2019s disease by activating GPX4","volume":"14","author":"Yong","year":"2024","journal-title":"Theranostics"},{"key":"B53","doi-asserted-by":"publisher","first-page":"4815","DOI":"10.1002\/ptr.8060","article-title":"Thonningianin A from Penthorum chinense Pursh as a targeted inhibitor of Alzheimer\u2019s disease-related \u03b2-amyloid and Tau proteins","volume":"38","author":"Yu","year":"2024","journal-title":"Phytother. Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1002\/med.21734","article-title":"Small molecules regulating reactive oxygen species homeostasis for cancer therapy","volume":"41","author":"Zhang","year":"2021","journal-title":"Med. Res. Rev."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1038\/s41419-022-05444-x","article-title":"Endoplasmic reticulum stress-mediated cell death in liver injury","volume":"13","author":"Zhang","year":"2022","journal-title":"Cell. Death Dis."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1389654","DOI":"10.3389\/fphar.2024.1389654","article-title":"Thonningianin A ameliorated renal interstitial fibrosis in diabetic nephropathy mice by modulating gut microbiota dysbiosis and repressing inflammation","volume":"15","author":"Zhang","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2588","DOI":"10.1039\/c5fo00388a","article-title":"Effects of thonningianin A in natural foods on apoptosis and cell cycle arrest of HepG-2 human hepatocellular carcinoma cells","volume":"6","author":"Zhang","year":"2015","journal-title":"Food Funct."},{"key":"B58","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.freeradbiomed.2021.09.008","article-title":"Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells","volume":"175","author":"Zhao","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"B59","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s41232-022-00209-7","article-title":"Targeting microglial autophagic degradation of the NLRP3 inflammasome for identification of thonningianin A in Alzheimer's disease","volume":"42","author":"Zhou","year":"2022","journal-title":"Inflamm. Regen."},{"key":"B60","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.apsb.2020.06.016","article-title":"SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation","volume":"11","author":"Zhou","year":"2021","journal-title":"Acta Pharm. Sin. B"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1531277\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T06:42:06Z","timestamp":1740033726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1531277\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":60,"alternative-id":["10.3389\/fphar.2025.1531277"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1531277","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,20]]},"article-number":"1531277"}}