Myricitrin alleviates paraquat-induced acute lung injury via PERK pathway to attenuate endoplasmic reticulum stress and mitochondrial dysfunction.

Paraquat (PQ) poisoning causes high mortality due to acute lung injury (ALI) and respiratory failure, with no specific antidote available. Myricitrin, a natural flavonol showing antioxidative properties, demonstrates potential against PQ toxicity, yet its exact protective mechanisms in PQ-induced ALI remain unclear. In this study, we investigated the therapeutic effects and mechanisms of myricitrin against PQ-induced ALI using BEAS-2B cells and C57BL/6J mice. Myricitrin significantly attenuated oxidative stress, reduced apoptosis, and restored mitochondrial function in PQ-injured BEAS-2B cells, while also improving survival and mitigating pathological damage in the lung tissues of mice. Mechanistically, myricitrin was suggested to interact with PERK and inhibited its autophosphorylation, thereby suppressing the downstream PERK- eIF2α-ATF4-CHOP signaling axis. This inhibition alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction, ultimately exerting a protective effect. Furthermore, myricitrin mitigated oxidative stress and associated ER damage through its intrinsic antioxidant capacity, which acted in synergy with its inhibition of the PERK pathway. Collectively, our findings demonstrate that myricitrin protects against PQ-induced ALI primarily through inhibition of the PERK signaling pathway, thereby suppressing the ER stress and mitochondrial-mediated apoptosis, supporting its therapeutic potential for this life-threatening condition.