Squalene epoxidase promotes paraquat-induced pulmonary toxicity through endoplasmic reticulum-mediated ferroptosis.

INTRODUCTION: Paraquat (PQ), a widely used herbicide, causes lethal lung injury through unresolved mechanisms, posing urgent clinical challenges due to the lack of effective antidotes. OBJECTIVES: This study aimed to define the role of squalene epoxidase (SQLE) in PQ-induced ferroptosis and endoplasmic reticulum (ER) stress, and to evaluate the therapeutic efficacy of the SQLE inhibitor liranaftate (LNT). METHODS: Cytotoxicity was assessed via CCK-8, ATP assays, and PI staining. Labile iron levels and lipid peroxidation were quantified using flow cytometry. ER morphology was visualized with ER-Tracker Green, mitochondrial swelling with MitoTracker Green, and ferrous iron localization with FerroOrange Live Cell Dye. Iron donors (FeSO(4), FeCl(3), ferric ammonium citrate) were used to modulate ferroptosis. In vivo therapeutic effects of LNT were evaluated in PQ-induced acute lung injury (ALI) mouse models. RESULTS: PQ triggered ferroptosis via ER stress-dependent PERK/eIF2α activation, with SQLE identified as a key mediator. LNT suppressed PQ-induced cytotoxicity by reducing labile iron, lipid peroxidation, and ER/mitochondrial damage. Iron supplementation exacerbated ferroptosis, while LNT restored GPX4 and SLC7A11 expression. In vivo, LNT treatment significantly improved survival rates from 45% in the PQ model group to 95%, while attenuating ALI severity by blocking the PERK signaling pathway and upregulating the ferroptosis-related proteins GPX4 and SLC7A11. CONCLUSION: These findings highlight the potential role of ferroptosis and SQLE in mediating PQ toxicity and provide therapeutic strategies to combat PQ toxicity by inhibiting ferroptosis and/or targeting SQLE. Repurposing LNT may be a potential antidote for PQ-induced ALI.