{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:59:41Z","timestamp":1790704781699,"version":"4.1.0"},"reference-count":56,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Zhejiang Province","award":["LZYQ25H270001"],"award-info":[{"award-number":["LZYQ25H270001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmazie"],"abstract":"<jats:p>Background: Ferroptosis has been recognized as an important pathological mechanism underlying ischemic stroke (IS). However, the precise mechanisms underlying the neuroprotective effects of Hydroxysafflor yellow A (HSYA) in IS remain unclear. Objective: Therefore, this study aimed to investigate the protective effects of HSYA against IS and explore the underlying ferroptosis-related mechanisms. Methods: An integrated strategy combining network pharmacology, molecular docking, molecular dynamics simulations, and a middle cerebral artery occlusion (MCAO) mouse model was employed to elucidate the neuroprotective mechanisms of HSYA. Neurological deficit scores, infarct volume, histopathology, oxidative stress, and ferroptosis-related molecules were evaluated. For in vivo validation, mice were randomly assigned to the sham, MCAO, Ras-selective lethal (RSL), HSYA, and RSL + HSYA groups (n = 12 per group). Ras-selective lethal 3 (RSL3) was used as a glutathione peroxidase 4 (GPX4) inhibitor in the RSL and RSL + HSYA groups. Results: Network pharmacology identified GPX4 and Ferritin Heavy Chain 1 (FTH1) as potential ferroptosis-related targets of HSYA in IS. Docking analysis showed favorable binding affinities of HSYA toward GPX4 (\u22129.3 kcal\/mol) and FTH1 (\u22129.1 kcal\/mol), and molecular dynamics simulations further supported the stability of the HSYA\u2013GPX4 and HSYA\u2013FTH1 complexes. In vivo experiments showed that HSYA significantly improved neurological deficit score, reduced infarct volume, and alleviated histopathological damage in MCAO mice (p &lt; 0.01 or p &lt; 0.05). Moreover, HSYA significantly decreased malondialdehyde (MDA) and reactive oxygen species (ROS) levels while increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities (p &lt; 0.01 or p &lt; 0.05). HSYA significantly upregulated the mRNA and protein levels of GPX4, FTH1, and mitochondrial ferritin (FTMT) (p &lt; 0.01 or p &lt; 0.05). Notably, HSYA significantly increased the relative protein expression of GPX4 compared with the MCAO group (p &lt; 0.01). Furthermore, RSL3 partially attenuated the protective effects of HSYA on cerebral injury, oxidative stress, and the expression of GPX4, FTH1, and FTMT (p &lt; 0.01 or p &lt; 0.05). Collectively, the present study demonstrates that HSYA confers neuroprotection against IS, at least in part, through regulation of GPX4-associated ferroptosis pathways. Conclusions: HSYA provides significant neuroprotection against IS. These effects may be mediated, at least in part, through GPX4-associated ferroptosis pathways and the maintenance of iron homeostasis, thereby advancing understanding of its antioxidant mechanisms and supporting its therapeutic potential for IS.<\/jats:p>","DOI":"10.31083\/pharmazie55314","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:05:53Z","timestamp":1790701553000},"source":"Crossref","is-referenced-by-count":0,"title":["Hydroxysafflor Yellow A Alleviates Ischemic Stroke Through Modulation of GPX4-Associated Ferroptosis: Computational Simulation and Animal Validation"],"prefix":"10.31083","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3803-3978","authenticated-orcid":true,"given":"Yun","family":"Chen","sequence":"first","affiliation":[{"name":"The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People\u2019s Hospital, 310053 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2805-8225","authenticated-orcid":true,"given":"Tianxue","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China"},{"name":"Zhejiang Key Laboratory of Chinese Medicine for Cardiovascular and Cerebrovascular Disease, 310053 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4133-5483","authenticated-orcid":true,"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"name":"The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People\u2019s Hospital, 310053 Hangzhou, Zhejiang, China"},{"name":"School of Basic Medical Sciences, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Owolabi MO, Thrift AG, Mahal A, Ishida M, Martins S, Johnson WD, et al. 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