Procyanidin B2 alleviates oxidative stress and ferroptosis in sepsis‑associated acute lung injury by activating PI3K/GSK3β/Nrf2 pathway

Background: Sepsis has attracted considerable attention due to its high mortality rate. Ferroptosis is a form of cell death dependent on ferrous ions and lipid peroxides, which plays a crucial role in sepsis-associated acute lung injury (ALI). Procyanidin B2 (PCB2), widely present in various plants and fruits, has been demonstrated to possess anti-inflammatory and antioxidant properties. However, the molecular mechanisms by which PCB2 exerts protective effects against sepsis through the Nrf2 signaling pathway and ferroptosis remain unclear. Materials and methods: In vitro, the protective effects of PCB2 on A549 cells were evaluated using CCK-8, ROS detection, mitochondrial membrane potential assessment, Fe²⁺ content measurement, immunofluorescence, and flow cytometry. In vivo, the therapeutic effect of PCB2 on ALI was assessed using H&E staining and Western blotting. Results: PCB2 effectively alleviated ALI by reducing the lung wet-to-dry (W/D) ratio and improving histopathological changes. Both in vitro and in vivo, PCB2 activated the PI3K/GSK3β/c-Myc signaling pathway, promoted Nrf2 nuclear translocation, and increased the expression of downstream Nrf2 target proteins. Moreover, PCB2 significantly reduced LPS-induced apoptosis, ROS production, Fe²⁺ accumulation, and enhanced mitochondrial membrane potential. Conclusion: Our findings suggested that PCB2 activated the PI3K/GSK3β/c-Myc signaling pathway and promoted Nrf2 expression and its downstream target proteins, thereby alleviated oxidative stress and ferroptosis in sepsis‑associated ALI. Therefore, this study will provide a theoretical basis for the treatment of ALI with PCB2.