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In this study, we investigated the protective effects of wine\u2010processed <jats:italic>Polygonatum sibiricum<\/jats:italic> (WP. <jats:italic>P. sibiricum<\/jats:italic>) against cisplatin\u2010induced acute kidney injury (DDP\u2010AKI) using an integrated approach combining UPLC\u2010Q\u2010TOF\u2010MS\/MS analysis, network pharmacology, molecular docking and in\u00a0vivo\/vitro experimental validation. The WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic> extract demonstrated dose\u2010dependent renal protection in mice with DDP\u2010AKI, significantly attenuating weight loss (<jats:italic>p\u2009&lt;<\/jats:italic>\u20090.05), improving renal function (reduced serum BUN by 29.2%\u201338.9% and CRE by 8.0%\u201336.7%), reducing tubular necrosis and biomarkers (NGAL decreased 49.2%\u201386.6%, <jats:italic>p\u2009&lt;<\/jats:italic>\u20090.01), while showing no hepatotoxicity. In addition, WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic> elevated SOD activity by 15.5%\u201328.5% and reduced MDA levels by 13.5%\u201326.9% (<jats:italic>p\u2009&lt;<\/jats:italic>\u20090.01). UPLC\u2010Q\u2010TOF\u2010MS\/MS analysis elucidated eight bioactive components (e.g., flavonoids and glycosides). Network pharmacology revealed 132 targets shared by WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic> and DDP\u2010AKI, such as mTOR, STAT3 and PPAR. Molecular docking confirmed strong binding (\u2264\u2009\u22126.0\u2009kcal\u00b7mol<jats:sup>\u22121<\/jats:sup>) between core components and targets. Mechanistically, WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic> activated the mTOR pathway (<jats:italic>p\u2009&lt;<\/jats:italic>\u20090.01) and suppressed apoptosis (<jats:italic>p\u2009&lt;<\/jats:italic>\u20090.01), with effects comparable or superior to those of NAC. This study is the first to validate the nephroprotective effect of WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic>, linking its multi\u2010target effects (mTOR\/ROS\/apoptosis) to enhanced phytochemical potency. These findings support WP. <jats:italic>P<\/jats:italic>. <jats:italic>sibiricum<\/jats:italic> as a clinically translatable adjuvant for DDP\u2010AKI.<\/jats:p>","DOI":"10.1111\/bcpt.70092","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T15:19:54Z","timestamp":1756135194000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi\u2010Target Renal Protection of Wine\u2010Processed <i>Polygonatum <scp>sibiricum<\/scp><\/i> Against Cisplatin\u2010Induced Nephrotoxicity: Integrated Phytochemistry, Network Pharmacology and Experimental Validation"],"prefix":"10.1111","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2518-335X","authenticated-orcid":false,"given":"Yu","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Shaanxi University of Chinese Medicine  Xianyang Shaanxi 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