{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:41:50Z","timestamp":1778287310615,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"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. Chem."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The Wenpitongluo Decoction (WPTLD) was a classical herbal formula composed of medicinal herbs with both edible and therapeutic properties. It demonstrated clinical efficacy in treating Cardiorenal Syndrome (CRS), though its mechanism of action remained unclear. Although inflammatory and oxidative stress pathways in CRS have been intensively studied, the roles of ferroptosis and anoikis, which may be activated by these pathways, have received little attention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, the active components of WPTLD were obtained through the TCMSP and Herb databases, and then identified using UHPLC-HRMS. Subsequently, target prediction of the identified components was carried out via the SwissTargetPrediction platform. While CRS-related targets were retrieved from GEO, GeneCards, and PharmGKB. A gene library of ferroptosis- and anoikis-associated targets was established. Tissue-specific mRNA expression profiles were analyzed via BioGPS. Subsequently, protein-protein interaction (PPI) networks were constructed to identify core targets, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using Metascape. Finally, molecular docking assessed binding affinities between active components and core targets, with top-ranked complexes undergoing molecular dynamics (MD) simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifteen bioactive components and 39 component-disease interaction targets were identified, predominantly localized in kidney, thymus, lung, adipocytes, adrenal gland, and heart tissues. Topological analysis of PPI networks revealed eight core targets, including ferroptosis-\/anoikis-associated SIRT1, PTGS2, and PRKCA. KEGG analysis highlighted critical pathways such as AMPK and PI3K-Akt signaling. Notably, molecular docking and MD simulations demonstrated stable binding between active compounds and core targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study systematically deciphers WPTLD\u2019s anti-CRS mechanisms via targeting ferroptosis- and anoikis-related genes through multi-pathway modulation. These findings not only clarify the pathological roles of ferroptosis and anoikis in CRS but also provide a computational framework for developing therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fchem.2025.1617676","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:30:15Z","timestamp":1753093815000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrative UHPLC-HRMS and computational biology reveal ferroptosis and anoikis targeting by Wenpitongluo decoction in cardiorenal syndrome"],"prefix":"10.3389","volume":"13","author":[{"given":"Xinxin","family":"Mao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuqing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunmei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingxuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingqiao","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1083\/jcb.152.3.633","article-title":"Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis","volume":"152","author":"Aoudjit","year":"2001","journal-title":"J. Cell Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1093\/ndt\/gfq066","article-title":"Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference","volume":"25","author":"Bagshaw","year":"2010","journal-title":"Nephrol. Dial. Transpl."},{"key":"B4","doi-asserted-by":"publisher","first-page":"113914","DOI":"10.1016\/j.intimp.2024.113914","article-title":"ADSCs-derived exosomes suppress macrophage ferroptosis via the SIRT1\/NRF2 signaling axis to alleviate acute lung injury in sepsis","volume":"146","author":"Bai","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e05921","DOI":"10.1016\/j.heliyon.2021.e05921","article-title":"Ellagic acid restored lead-induced nephrotoxicity by anti-inflammatory, anti-apoptotic and free radical scavenging activities","volume":"7","author":"Bhattacharjee","year":"2021","journal-title":"Heliyon"},{"key":"B6","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/s0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"395","author":"Bikbov","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"103321","DOI":"10.1016\/j.redox.2024.103321","article-title":"Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis","volume":"76","author":"Chen","year":"2024","journal-title":"Redox Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1080\/02656736.2022.2094476","article-title":"SIRT1-mediated p53 deacetylation inhibits ferroptosis and alleviates heat stress-induced lung epithelial cells injury","volume":"39","author":"Chen","year":"2022","journal-title":"Int. J. Hyperth."},{"key":"B9","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41419-023-05716-0","article-title":"The interaction between ferroptosis and inflammatory signaling pathways","volume":"14","author":"Chen","year":"2023","journal-title":"Cell Death Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.ijcard.2015.03.438","article-title":"SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells","volume":"189","author":"De Angelis","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B12","first-page":"853","article-title":"Protective effect of isorhamnetin on H9C2 cell line against oxidative stress","volume":"31","author":"Dong","year":"2015","journal-title":"Chin. Pharmacol. Bull."},{"key":"B13","doi-asserted-by":"publisher","first-page":"025304","DOI":"10.1103\/physreve.104.025304","article-title":"Steepest-descent algorithm for simulating plasma-wave caustics via metaplectic geometrical optics","volume":"104","author":"Donnelly","year":"2021","journal-title":"Phys. Rev. E"},{"key":"B14","doi-asserted-by":"publisher","first-page":"628988","DOI":"10.3389\/fphar.2021.628988","article-title":"Baicalin prevents myocardial ischemia\/reperfusion injury through inhibiting ACSL4 mediated ferroptosis","volume":"12","author":"Fan","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.jacc.2003.07.031","article-title":"Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure","volume":"43","author":"Forman","year":"2004","journal-title":"J. Am. Coll. Cardiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1053\/j.ajkd.2011.07.023","article-title":"Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics","volume":"58","author":"Freda","year":"2011","journal-title":"Am. J. Kidney Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"B18","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature14344","article-title":"Ferroptosis as a p53-mediated activity during tumour suppression","volume":"520","author":"Jiang","year":"2015","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"101509","DOI":"10.1016\/j.cpcardiol.2022.101509","article-title":"Recent developments in the evaluation and management of cardiorenal syndrome: a comprehensive review","volume":"48","author":"Kim","year":"2023","journal-title":"Curr. Probl. Cardiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types","volume":"114","author":"Klauda","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"B21","doi-asserted-by":"publisher","first-page":"973","DOI":"10.2147\/jir.s498820","article-title":"Identification of anoikis-related genes in chronic kidney disease based on bioinformatics analysis combined with experimental validation","volume":"18","author":"Liu","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"421","DOI":"10.16016\/j.2097-0927.202107152","article-title":"TSSC3 suppresses fibrosis of renal tubular epithelium by regulating PI3K\/Akt signaling pathway and anoikis resistance in myofibroblasts","volume":"44","author":"Liu","year":"2022","journal-title":"J. Army Med. Univ."},{"key":"B23","doi-asserted-by":"publisher","first-page":"116220","DOI":"10.1016\/j.jep.2023.116220","article-title":"Effects of modified Huangqi Chifeng decoction on the IL-17 signaling pathway in an IgA nephropathy rat model","volume":"307","author":"Ma","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"933","DOI":"10.2215\/cjn.0000000000000064","article-title":"Cardiorenal syndrome in the hospital","volume":"18","author":"McCallum","year":"2023","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1161\/01.atv.0000099882.52647.e4","article-title":"Ano\u00efkis in the cardiovascular system: known and unknown extracellular mediators","volume":"23","author":"Michel","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3354","DOI":"10.1021\/ct2002732","article-title":"Comparison of tetrahedral order, liquid state anomalies, and hydration behavior of mTIP3P and TIP4P water models","volume":"7","author":"Nayar","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"B27","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1159\/000441283","article-title":"Current and potential therapeutic strategies for hemodynamic cardiorenal syndrome","volume":"6","author":"Obi","year":"2016","journal-title":"Cardiorenal Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1007\/s00894-010-0650-7","article-title":"An improved generalized AMBER force field (GAFF) for urea","volume":"16","author":"\u00d6zp\u0131nar","year":"2010","journal-title":"J. Mol. Model"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e28954","DOI":"10.1016\/j.heliyon.2024.e28954","article-title":"Baicalein improves renal interstitial fibrosis by inhibiting the ferroptosis in vivo and in vitro","volume":"10","author":"qiang","year":"2024","journal-title":"Heliyon"},{"key":"B30","doi-asserted-by":"publisher","first-page":"8194690","DOI":"10.1155\/2016\/8194690","article-title":"Cardioprotective effects of astragalin against myocardial ischemia\/reperfusion injury in isolated rat heart","volume":"2016","author":"Qu","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e840","DOI":"10.1161\/cir.0000000000000664","article-title":"Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American heart association","volume":"139","author":"Rangaswami","year":"2019","journal-title":"Circulation"},{"key":"B32","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1093\/eurheartj\/ehp507","article-title":"Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative","volume":"31","author":"Ronco","year":"2010","journal-title":"Eur. Heart J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e34446","DOI":"10.1097\/md.0000000000034446","article-title":"Exploration of the possible mechanisms of Ling Gui Zhu Gan decoction in nephrotic syndrome based on network pharmacology, molecular docking and molecular dynamics simulation","volume":"102","author":"Shi","year":"2023","journal-title":"Med. Baltim."},{"key":"B34","doi-asserted-by":"publisher","first-page":"6200","DOI":"10.1038\/s41598-025-89895-0","article-title":"In vivo and in vitro investigations of schisandrin B against angiotensin II induced ferroptosis and atrial fibrosis by regulation of the SIRT1 pathway","volume":"15","author":"Shi","year":"2025","journal-title":"Sci. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1083\/jcb.200106070","article-title":"Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins","volume":"155","author":"Stupack","year":"2001","journal-title":"J. Cell Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"115366","DOI":"10.1016\/j.jep.2022.115366","article-title":"An integrated approach for investigating pharmacodynamic material basis of Lingguizhugan Decoction in the treatment of heart failure","volume":"295","author":"Sun","year":"","journal-title":"J. Ethnopharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"113162","DOI":"10.1016\/j.biopha.2022.113162","article-title":"Daming capsule protects against myocardial infarction by promoting mitophagy via the SIRT1\/AMPK signaling pathway","volume":"151","author":"Sun","year":"","journal-title":"Biomed. Pharmacother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1002\/path.3000","article-title":"Anoikis: an emerging hallmark in health and diseases","volume":"226","author":"Taddei","year":"2012","journal-title":"J. Pathol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: fast, flexible, and free","volume":"26","author":"Van Der Spoel","year":"2005","journal-title":"J. Comput. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e13250","DOI":"10.1111\/wrr.13250","article-title":"Kaempferol promotes flap survival by inhibiting ferroptosis and inflammation through network pharmacology and in vivo experiments","volume":"33","author":"Wang","year":"2025","journal-title":"Wound Repair Regen."},{"key":"B41","first-page":"1801","article-title":"Research progress of AMPK regulating ferroptosis related signaling pathway","volume":"39","author":"Wang","year":"","journal-title":"Chin. Pharmacol. Bull."},{"key":"B42","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.ijcard.2022.12.018","article-title":"Baicalein and luteolin inhibit ischemia\/reperfusion-induced ferroptosis in rat cardiomyocytes","volume":"375","author":"Wang","year":"","journal-title":"Int. J. Cardiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41420-022-00931-8","article-title":"Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5\/6 nephrectomy-induced CKD rat model","volume":"8","author":"Wang","year":"","journal-title":"Cell Death Discov."},{"key":"B44","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/s41420-022-01183-2","article-title":"Emerging roles of ferroptosis in cardiovascular diseases","volume":"8","author":"Wang","year":"","journal-title":"Cell Death Discov."},{"key":"B45","first-page":"3146","article-title":"Mechanism of action of Linggui Zhugan Decoction in treatment of cardiovascular diseases","volume":"55","author":"Wang","year":"2024","journal-title":"Chin. Traditional Herb. Drugs"},{"key":"B46","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.bbrc.2016.03.052","article-title":"Identification of baicalein as a ferroptosis inhibitor by natural product library screening","volume":"473","author":"Xie","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B47","doi-asserted-by":"publisher","first-page":"155409","DOI":"10.1016\/j.phymed.2024.155409","article-title":"Roles of flavonoids in ischemic heart disease: cardioprotective effects and mechanisms against myocardial ischemia and reperfusion injury","volume":"126","author":"Xu","year":"2024","journal-title":"Phytomedicine"},{"key":"B48","doi-asserted-by":"publisher","first-page":"116833","DOI":"10.1016\/j.ecoenv.2024.116833","article-title":"Ellagic acid ameliorates arsenic-induced neuronal ferroptosis and cognitive impairment via Nrf2\/GPX4 signaling pathway","volume":"283","author":"Yang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B49","doi-asserted-by":"publisher","first-page":"110607","DOI":"10.1016\/j.cbi.2023.110607","article-title":"Baicalein ameliorates polymyxin B-induced acute renal injury by inhibiting ferroptosis via regulation of SIRT1\/p53 acetylation","volume":"382","author":"Yu","year":"2023","journal-title":"Chem. Biol. Interact."},{"key":"B50","doi-asserted-by":"publisher","first-page":"114795","DOI":"10.1016\/j.jep.2021.114795","article-title":"Efficacy of Modified Huangqi Chifeng decoction in alleviating renal fibrosis in rats with IgA nephropathy by inhibiting the TGF-\u03b21\/Smad3 signaling pathway through exosome regulation","volume":"285","author":"Zhao","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"117520","DOI":"10.1016\/j.jep.2023.117520","article-title":"Ameliorative effects of Modified Huangqi Chifeng decoction on podocyte injury via autophagy mediated by PI3K\/AKT\/mTOR and AMPK\/mTOR pathways","volume":"321","author":"Zhao","year":"2024","journal-title":"J. Ethnopharmacol."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1617676\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:30:17Z","timestamp":1753093817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1617676\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":51,"alternative-id":["10.3389\/fchem.2025.1617676"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2025.1617676","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,21]]},"article-number":"1617676"}}