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Immunol."],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is a global health crisis driven by oxidative stress and immune dysregulation. Emerging evidence positions ferroptosis\u2014an iron-dependent cell death driven by iron-catalyzed peroxidation of esterified polyunsaturated fatty acids (PUFAs) in membrane phospholipids\u2014as 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)\u2014a byproduct of lipid peroxidation\u2014serving 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1630969","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:25:12Z","timestamp":1772169912000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic 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