Hesperetin alleviates PM2.5-induced lung injury by inhibiting ferroptosis in an Nrf2-dependent manner.

BACKGROUND

Fine particulate matter (PM2.5) is a global environmental problem that threatens public health because it can induce ferroptosis and cause lung injury. Hesperetin (Hes), a natural compound widely present in fruits and vegetables, can activate nuclear factor erythroid 2-related factor 2 (Nrf2), thereby exerting powerful antioxidant effects.

PURPOSE: We explored the antioxidant effects of Hes on lung injury caused by PM2.5 exposure.

METHODS

In vivo, a mouse model of PM2.5-induced lung injury was used to evaluate the protective effect of Hes. In vitro, the effects of Hes on PM2.5-induced ferroptosis were examined in BEAS-2B cells.

RESULTS

In vivo, Hes activated the Nrf2 signaling pathway and protected lung tissues from damage induced by PM2.5. In vitro, Hes activated Nrf2 by promoting PI3K/AKT phosphorylation and inhibiting PM2.5-induced ferroptosis. However, in siNrf2-treated BEAS-2B cells, the protective effects of Hes were eliminated. In addition, Nrf2-KO mice exhibited more severe lung injury than did wild-type (WT) mice after PM2.5 exposure. Besides, the protective effects of Hes on PM2.5-exposed Nrf2-KO mice were strongly compromised.

CONCLUSION

Hes activates Nrf2 by promoting PI3K/AKT phosphorylation to exert a protective effect on PM2.5-induced ferroptosis and lung injury.