{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:19:53Z","timestamp":1783412393522,"version":"3.54.6"},"reference-count":67,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"14th Five-Year National Key R&D Project","award":["2024YFD1800200"],"award-info":[{"award-number":["2024YFD1800200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Global warming has increasingly positioned heat stress (HS) as a major threat to public health, as it can inflict damage on multiple organs including the kidneys, liver, and heart. However, effective targeted therapeutic strategies remain limited. This investigation employed an integrated approach combining Network pharmacology, in silico binding simulations, and cell-based assays to elucidate the cytoprotective properties and molecular basis of oxymatrine action under heat-stressed conditions. Network analysis identified 36 overlapping targets common to oxymatrine and the pathological processes of HS-related acute kidney injury (AKI), acute liver injury (ALI), and acute myocardial injury (AMI). These targets were strongly enriched in the PI3K-AKT signaling cascade. Molecular docking showed that oxymatrine binds tightly to key pathway proteins such as PIK3CA and GSK3B, with Vina scores below \u22128 kcal\/mol. In 293T cells, the half-maximal cytotoxic concentration (CC50) of oxymatrine exceeded 2000 \u03bcM. Under heat stress, oxymatrine (31.25\u20131000 \u03bcM) dose-dependently increased cell viability by about 30% and significantly lowered HSP90 and HSP70 expression. Similar protective effects were observed in H9C2 cardiomyocytes under heat stress. RT-qPCR further confirmed that oxymatrine reduced the transcript levels of PI3K-AKT pathway-related genes, including CASP3, EGFR, RXR\u03b1, and MMP9 in 293T cells. We also found 18 overlapping targets between oxymatrine and ferroptosis, most of which matched the core targets above. Molecular docking analysis predicted binding of oxymatrine to the ferroptosis regulator GPX4. Together, these results suggested that oxymatrine potentially alleviates HS injury by modulating the PI3K-AKT signaling pathway andregulating potential ferroptotic targets such as GPX4.<\/jats:p>","DOI":"10.3390\/ijms27135919","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"5919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Potential Mechanism of Oxymatrine in Alleviating Heat Stress Injury Based on Network Pharmacology, Molecular Docking, and In Vitro Validation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1204-2873","authenticated-orcid":false,"given":"Sheng","family":"Cheng","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Qiu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-5754","authenticated-orcid":false,"given":"Guangneng","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiang","family":"Xin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev.publhealth.29.020907.090843","article-title":"Heat stress and public health: A critical review","volume":"29","author":"Kovats","year":"2008","journal-title":"Annu. 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