He_2026_Biomed.Environ.Sci_39_342

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).