NADPH oxidase-dependent heme oxygenase-1 expression mediates cigarette smoke-induced ferroptosis via intracellular Fe(II) accumulation

Jun 2, 2025Free radical biology & medicine

How cigarette smoke may cause cell death by increasing iron inside cells through NADPH oxidase and heme oxygenase-1

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Abstract

Enhanced lipid peroxidation and iron accumulation were observed in the lungs of COPD mice.

Ferroptosis is associated with chronic obstructive pulmonary disease (COPD) pathogenesis, though its exact role remains unclear.
Cigarette smoke extract (CSE) treatment reduced cell viability and levels of the ferroptosis-related protein glutathione peroxidase 4 (GPX4) in bronchial epithelial cells.
CSE increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and total iron, indicating heightened oxidative stress.
Inhibition of ferroptosis using compounds like ferrostatin-1 (Fer-1) and deferoxamine (DFO) completely reversed CSE-induced effects.
CSE promoted the expression of various target genes of the nuclear factor erythroid 2-related factor 2 (Nrf2), particularly heme oxygenase-1 (HO-1).
HO-1 is highlighted as a crucial mediator of ferroptosis in COPD, suggesting its potential as a therapeutic target.

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Ferroptosis is a novel form of programmed cell death characterized by reactive oxygen species (ROS) generation, lipid peroxidation, and iron accumulation. Although ferroptosis has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, its precise role in this condition is still unclear. Additionally, key pathogenic factors contributing to ferroptosis in COPD are still debated. We aimed to investigate the relationship between ferroptosis and COPD, and elucidate the potential underlying mechanisms. In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with cigarette smoke extract (CSE) and ferroptosis inhibitors such as ferrostatin-1 (Fer-1), iron chelator (deferoxamine; DFO), zinc protoporphyrin IX (ZnPP), and heme oxygenase-1 (HO-1) inhibitor. Cell viability was measured using CCK-8 and Calcein-AM staining. Malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), iron, and ferroptosis-related protein levels, such as glutathione peroxidase 4 (GPX4), were measured. To validate these results, a COPD mouse model was induced by CSE, and ferroptosis levels in lung tissues were evaluated. Enhanced lipid peroxidation was observed in the lungs, along with enhanced HO-1 level and reduced GPX4 level. CSE treatment downregulated BEAS-2B cell viability and GPX4. CSE also increased MDA, 4-HNE, and total iron levels. Fer-1, DFO, and NAC completely abolished CSE-induced ferroptosis. Furthermore, CSE induced the expression of various nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, particularly HO-1. ZnPP treatment and HO-1 knockdown alleviated CSE-induced cell death, whereas HO-1 overexpression reduced cell viability and induced ferroptosis. These findings suggest that CS-induced ferroptosis significantly contributes to COPD development, with HO-1 acting as a crucial mediator of this process. HO-1 regulates ferroptosis through its role in cellular redox and iron accumulation, highlighting it as a potential therapeutic target in COPD management.

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NADPH oxidase-dependent heme oxygenase-1 expression mediates cigarette smoke-induced ferroptosis via intracellular Fe(II) accumulation

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