Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis

TLDR

Ferroptosis, a necrotic cell death driven by iron‑mediated lipid peroxidation, and disrupted iron homeostasis that heightens oxidative stress are implicated in COPD pathogenesis. The study demonstrates that ferroptosis contributes to COPD pathogenesis. In vivo and in vitro models reveal that cigarette smoke induces labile iron accumulation, lipid peroxidation, and non‑apoptotic cell death, all of which are counteracted by GPx4 activity. Treatment with iron chelators, ferroptosis inhibitors, and GPx4 manipulation, along with evidence of NCOA4‑mediated ferritinophagy, confirms that cigarette smoke‑induced ferroptosis drives COPD pathogenesis.

Abstract

Abstract Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.