Paraquat-induced ferroptosis suppression via NRF2 expression regulation

Paraquat (PQ) is an environmentally friendly and efficient herbicide, but PQ misuse or intentional self-use can cause death through multiple organ damage and can cause acute lung injury. Existing clinical treatments alleviate symptoms but do not significantly improve the mortality rate. Ferroptosis is a type of necrosis that presents in a manner very similar to the cell damage induced by high doses of PQ, but the role of ferroptosis in paraquat-induced lung injury remains unclear. In this study, we aimed to explore the role of ferroptosis in PQ-induced A549 cell injury and identify the potential mechanisms and critical sites of protection against PQ-induced A549 injury by ferroptosis inhibitors. We found that the ferroptosis inhibitors Ferr-1 and Lip-1 inhibit ferroptosis by attenuating oxidative stress through the upregulation of NRF2 gene expression. The protective role of the ferroptosis inhibitor Dfo was most evident in paraquat-induced cell injury. Dfo inhibited ferroptosis by iron chelation and promoted NRF2 protein level reduction. NRF2 attenuated PQ-induced ferroptosis in A549 cells, mainly through the upregulation of SLC40A1 to encourage the movement of iron to the extracellular side to alleviate iron overload, and the upregulation of SLC7A11 to promote the expression of GPX4 to inhibit lipid peroxidation.