Sipeimine ameliorates PM2.5-induced lung injury by inhibiting ferroptosis via the PI3K/Akt/Nrf2 pathway: A network pharmacology approach

Fine particulate matter (PM2.5) exposure can cause lung injury and a large number of respiratory diseases. Sipeimine is a steroidal alkaloid isolated from Fritillaria roylei which has been associated with anti-inflammatory, antitussive and antiasthmatic properties. In this study, we explored the potential effects of sipeimine against PM2.5-induced lung injury in Sprague Dawley rats. Sipeimine alleviated lung injury caused by PM2.5 and decreased pulmonary edema, inflammation and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid. In addition, sipeimine upregulated the glutathione (GSH) expression and downregulated the expression of 4-hydroxynonenal (4-HNE), tissue iron and malondialdehyde (MDA). The downregulation of proteins involved in Ferroptosis, including nuclear factor E2-related factor 2 (Nrf2), Glutathione Peroxidase 4 (GPX4), heme oxygenase-1 (HO-1) and solute carrier family 7 member 11 (SLC7A11) was reversed by sipeimine. The administration of RSL3, a potent ferroptosis-triggering agent, blocked the effects of sipeimine. Using network pharmacology, we found that the effects of sipeimine were presumably mediated through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. A PI3K Inhibitor (LY294002) blocked the PI3K/Akt signaling pathway and reversed the effects of sipeimine. Overall, this study suggested that the protective effect of sipeimine against PM2.5-induced lung injury was mainly mediated through the PI3K/Akt pathway, ultimately leading to a reduction in Ferroptosis.

Ferroptosis; Lung injury; Network pharmacology; PI3K/Akt/Nrf2; PM2.5; Sipeimine (PubChem CID: 442977).