REVIEW article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicOxidative Metabolism in Inflammation: Volume IIView all 5 articles
Ironing Out COPD: Ferroptosis-Driven Immune Dysregulation, Metabolic Rewiring, and Precision Therapeutic Opportunities
Provisionally accepted
- Affiliated Zhuhai Hospital, Southern Medical University, Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine, Zhuhai 519000, Guangdong, China., Zhuhai, China
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Chronic obstructive pulmonary disease (COPD) is a global health crisis driven by oxidative stress and immune dysregulation. Emerging evidence positions ferroptosis—an iron-dependent cell death driven by iron-catalyzed peroxidation of esterified polyunsaturated fatty acids (PUFAs) in membrane phospholipids—as a pivotal mediator of COPD pathogenesis. This review synthesizes cutting-edge insights into how cigarette smoke (CS) induces mitochondrial fission (via dynamin-related protein 1 (DRP1) phosphorylation) to exacerbate ferroptosis, potentially by enhancing lipid droplet (LD)-mitochondria contact sites and promoting lipid peroxidation in airway epithelial cells. This review further elucidates the complex and context-dependent role of nuclear factor erythroid 2-related factor 2 (Nrf2). While Nrf2 signaling is often suppressed globally in COPD lungs, its dysfunction in macrophages may paradoxically promote ferritinophagy-mediated iron retention through nuclear receptor coactivator 4 (NCOA4), overwhelming ferroprotein (FPN)-mediated iron export and unintentionally fueling ferroptosis. Clinically, plasma malondialdehyde (MDA)—a byproduct of lipid peroxidation—serving as a biomarker of oxidative stress severity, with elevated levels correlating with accelerated lung function decline in COPD patients. Therapeutically, promising targeted strategies are highlighted, such as inhaled exosomes loaded with liproxstatin-1, which can selectively inhibit pulmonary ferroptosis without inducing system immunosuppression. By bridging molecular mechanisms to therapeutic innovation, this review outlines a roadmap for precision medicine in COPD, focusing on the ferroptosis-immune axis to disrupt the self-perpetuating cycle of inflammation and tissue damage.
Keywords: COPD, ferroptosis, immune-metabolic crosstalk, Lipid Peroxidation, mitochondrial dynamics, Precision inhalation therapy
Received: 19 May 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Ni, Chen, Huang and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zebo Jiang
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