Polydatin Attenuates Sepsis-Induced Lung Injury by Inhibiting Neutrophil Extracellular Traps Formation via Nrf2/HO-1 Pathway

Background: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. Neutrophil extracellular traps (NETs) contribute to its pathogenesis. This study investigated whether polydatin (PD) protects against septic ALI by inhibiting NETs via the Nrf2/HO-1 pathway. Methods: A cecal ligation and puncture (CLP)-induced septic ALI mouse model and an LPS-stimulated neutrophil model were established. Lung injury was assessed by histology, lung wet/dry ratio, BALF protein, and inflammatory cytokines. Endothelial junction proteins and NETs markers were examined by Western blot, immunofluorescence, and SYTOX Green staining. Nrf2/HO-1 pathway activation and ML385 inhibitor experiments were performed for mechanistic validation. Results: PD dose-dependently attenuated lung injury, preserved endothelial junction proteins (ZO-1, VE-cadherin, occludin), and suppressed NETs formation in vivo. In vitro, PD activated Nrf2/HO-1, promoted Nrf2 nuclear translocation, reduced ROS, and inhibited LPS-induced NETs. These effects were abrogated by ML385, confirming pathway specificity. Conclusions: PD mitigates septic ALI by inhibiting NETs formation. In vitro mechanistic studies further suggest that this effect is mediated through activation of the Nrf2/HO-1 antioxidant pathway, positioning PD as a potential therapeutic candidate for sepsis-induced ALI.