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Although puerarin has demonstrated neuroprotective effects, the mechanisms underlying its therapeutic action on TBI via ferroptosis regulation remain unclear.\n                    <jats:bold>Objective:<\/jats:bold>\n                    This study aimed to elucidate the potential mechanisms by which puerarin exerts therapeutic effects on TBI, focusing on ferroptosis, through an integrative approach combining network pharmacology, MD simulations, and in vitro experiments.\n                    <jats:bold>Methods:<\/jats:bold>\n                    Potential targets of puerarin were predicted using TCMSP, PharmMapper, and SwissTargetPrediction, while ferroptosis- and TBI-related genes were retrieved from FerrDb, OMIM and GeneCards. Differential expression analysis of TBI-related genes was performed using the GSE58483 dataset from the GEO database. GO\/KEGG analysis were conducted using the Metascape platform. Molecular docking was carried out with AutoDock Vina and PyMol, followed by MD simulation using Gromacs 2022.6. In vitro experiments were conducted to further validate pathways and targets.\n                    <jats:bold>Results:<\/jats:bold>\n                    Key targets, including AKT1, ALB, IL6, and NFKB1, were identified and found to be primarily involved in inflammation-related signaling pathways such as TNF and IL-17. Molecular docking demonstrated stable interactions between puerarin and these targets, which were further supported by MD simulations showing good structural stability and low interaction energies. In HT22 cells subjected to glutamate\/erastin-induced ferroptosis, puerarin effectively counteracted ferroptotic cell damage.\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    The present investigation reveals that puerarin may inhibit ferroptosis by regulating the TNF signaling pathway, thereby alleviating TBI.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-53728-5","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:15:59Z","timestamp":1779689759000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network pharmacology analysis and cellular experiment validation of puerarin in attenuating TBI through suppression of ferroptosis"],"prefix":"10.1038","volume":"16","author":[{"given":"Qian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoli","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibing","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"53728_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-024-04940-0","volume":"28","author":"HC Yen","year":"2024","unstructured":"Yen, H. 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