Astragaloside II pretreatment alleviates PM2.5-induced lung injury in mice via MAPK/Nrf2/GPX4 axis-mediated suppression of ferroptosis
Liyun Liu, Zherui Shen, Nan Jia, Qian Chen, Chen Chen, Yi Luo, Xuemei Dai, Sijing Zhao, Caixia Pei, Demei Huang, Yilan Wang, Tao Shen, Z. H. Wan
Abstract
Exposure to fine particulate matter (PM2.5) induces inflammation and oxidative stress, contributing to respiratory diseases, including lung injury. Astragaloside II (AS II), a natural product derived from Astragali Radix (AR), demonstrates dual anti-inflammatory and antioxidant activities. This work systematically evaluates AS II's prophylactic efficacy and molecular pathways in mitigating PM2.5-triggered pulmonary damage using a murine model. Intratracheal PM2.5 suspension (7.5 mg/kg) was applied, with AS II (25 and 50 mg/kg) pretreated via intraperitoneal (i.p.) injection before the pollutant challenge. Results demonstrated that AS II alleviated PM2.5-induced lung injury, mitigated pulmonary edema and inflammation, and reduced levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). AS II upregulated glutathione (GSH) and catalase (CAT) levels while downregulating reactive oxygen species (ROS) and malondialdehyde (MDA). Mechanistically, AS II inhibited the mitogen-activated protein kinase (MAPK) signalling pathway, activated nuclear factor erythroid 2-related factor 2 (Nrf2), enhanced expression of glutathione peroxidase 4 (GPX4), and elevated other antioxidant proteins while suppressing ferroptosis and oxidative stress markers. To further validate the role of ferroptosis, RSL3-a small-molecule ferroptosis agonist that binds and inactivates GPX4-was employed. The protective efficacy of AS II against lung injury was effectively counteracted by RSL3-induced GPX4 inactivation. Collectively, AS II protects against PM2.5-induced pulmonary injury by modulating the MAPK/NRF2/GPX4 signaling axis to inhibit ferroptosis, thereby providing a novel therapeutic strategy for the treatment of PM2.5-associated pulmonary diseases.