Acteoside alleviates sepsis-induced acute lung injury by activating the Nrf2 pathway to inhibit ferroptosis.

Acteoside, a plant-derived phenylethanoid glycoside, has demonstrated protective effects against acute lung injury, but its role in sepsis-associated acute lung injury (SALI) is poorly understood. Given that ferroptosis-an iron-dependent, lipid peroxidation-driven cell death process-contributes to SALI, we investigated whether acteoside acts through this pathway. Our results show that acteoside alleviated histological damage, pulmonary edema, and inflammatory cell infiltration in an LPS-induced SALI model. It reduced levels of inflammatory mediators (TNF-α, IL-6, IL-1β, IFN-β) and exerted potent anti-ferroptotic effects, marked by enhanced SOD/GSH activity, decreased iron, GSSG, 4-HNE, and MDA, and restored expression of SLC7A11, GPX4, Nrf2, ACSL4, TfR1, and PTGS2. In RAW264.7 cells, acteoside similarly inhibited inflammation and ferroptosis. Crucially, the ferroptosis inducer erastin counteracted acteoside's benefits, whereas the Nrf2 inhibitor ML385 blocked its anti-ferroptotic action, confirming that acteoside alleviates SALI by targeting ferroptosis via Nrf2 activation.