Echinacoside inhibits ferroptosis and pyroptosis in ARDS through modulation of the KEAP1/NRF2/P62 signaling pathway

Background Acute respiratory distress syndrome (ARDS) remains a life-threatening pulmonary condition with persistently high mortality rates. Echinacoside (ECH) is a natural compound that has shown protective effects in experimental acute lung injury; however, the molecular mechanisms underlying its effects in ARDS remain incompletely understood. This study aimed to explore the potential mechanisms underlying the protective role of ECH in ARDS. Methods The protective effect of ECH on ARDS mice was evaluated. Subsequently, network pharmacology combined with RNA-sequencing was employed to identify mechanisms modulated by ECH. Finally, the mechanism of ECH on ARDS was verified in ARDS mice and mouse lung epithelial cells. Results ECH reduced the level of inflammatory response and alleviated lung injury in ARDS mice. Network pharmacology and RNA sequencing results suggested that its mechanism may be related to regulating inflammatory response, anti-oxidative stress, and inhibiting cell death. Further experiments indicated that ECH inhibited ferroptosis and pyroptosis, possibly through regulation of the KEAP1/NRF2 axis. Molecular dynamics, molecular docking, and protein-small molecule interaction verification demonstrated that ECH binds to the Kelch/DGR domain of KEAP1. Conclusions ECH binds to KEAP1 and may interfere with the KEAP1-NRF2 interaction, thereby promoting NRF2 release, which subsequently suppresses cellular pyroptosis and ferroptosis, ultimately reducing inflammation and lung injury. These findings support further investigation of ECH as a potential strategy for ARDS.