Multi‐Target Renal Protection of Wine‐Processed Polygonatum sibiricum Against Cisplatin‐Induced Nephrotoxicity: Integrated Phytochemistry, Network Pharmacology and Experimental Validation

ABSTRACT Acute kidney injury (AKI) is a serious complication of cisplatin chemotherapy, with limited treatment options. In this study, we investigated the protective effects of wine‐processed Polygonatum sibiricum (WP. P. sibiricum ) against cisplatin‐induced acute kidney injury (DDP‐AKI) using an integrated approach combining UPLC‐Q‐TOF‐MS/MS analysis, network pharmacology, molecular docking and in vivo/vitro experimental validation. The WP. P . sibiricum extract demonstrated dose‐dependent renal protection in mice with DDP‐AKI, significantly attenuating weight loss ( p < 0.05), improving renal function (reduced serum BUN by 29.2%–38.9% and CRE by 8.0%–36.7%), reducing tubular necrosis and biomarkers (NGAL decreased 49.2%–86.6%, p < 0.01), while showing no hepatotoxicity. In addition, WP. P . sibiricum elevated SOD activity by 15.5%–28.5% and reduced MDA levels by 13.5%–26.9% ( p < 0.01). UPLC‐Q‐TOF‐MS/MS analysis elucidated eight bioactive components (e.g., flavonoids and glycosides). Network pharmacology revealed 132 targets shared by WP. P . sibiricum and DDP‐AKI, such as mTOR, STAT3 and PPAR. Molecular docking confirmed strong binding (≤ −6.0 kcal·mol −1 ) between core components and targets. Mechanistically, WP. P . sibiricum activated the mTOR pathway ( p < 0.01) and suppressed apoptosis ( p < 0.01), with effects comparable or superior to those of NAC. This study is the first to validate the nephroprotective effect of WP. P . sibiricum , linking its multi‐target effects (mTOR/ROS/apoptosis) to enhanced phytochemical potency. These findings support WP. P . sibiricum as a clinically translatable adjuvant for DDP‐AKI.