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.