Ephx2 Deficiency Suppresses Chronic Obstructive Pulmonary Disease by Inhibiting Ferroptosis Caused by Cigarette Smoke via Regulation of the System Xc -/GSH/GPX4 Axis In Vivo

Objective: This study investigated the effect of reducing soluble Epoxide Hydrolase (sEH, encoded by the Ephx2 gene) on the mediation of EETs metabolism during Ferroptosis in emphysema in vivo.

Methods: Male C57BL/6J wild-type (WT) and Ephx2 ^-/- mice received whole-body exposure to either cigarette smoke (CS) or air for 16 weeks. The alveolar structure, pulmonary function, lung tissue morphology, cell death, and Ferroptosis levels were assessed following exposure.

Results: CS exposure caused emphysema, reduced pulmonary function, and induced Ferroptosis in mice compared with exposure to air. In contrast, following CS exposure, Ephx2 ^-/- mice exhibited significantly lower levels of emphysema, impaired lung function, lung cell death, intracellular iron, lipid Reactive Oxygen Species, cyclooxygenase-2, 4-hydroxynonenal, and malondialdehyde levels than those of WT mice. However, Ephx2 ^-/- mice exhibited higher levels of glutathione and ferritin heavy chain 1 than those of WT mice. SLC7A11 expression was significantly reduced, whereas Glutathione Peroxidase 4 expression was markedly increased in Ephx2 ^-/- mice compared with WT mice. Statistically significant differences ( P < 0.05) were observed.

Conclusion: These results suggest that Ephx2 deficiency inhibits Ferroptosis to alleviate CS-induced emphysema, primarily by mitigating its inhibitory effect on the cystine/glutathione/Glutathione Peroxidase 4 axis. Therefore, Ephx2 represents an effective therapeutic target in CS-induced chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease; Emphysema; Ephx2; Ferroptosis; System Xc-/GSH/GPX4 axis.