Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities

TL;DR

This paper explores how ferroptosis, a type of cell death involving iron and fats, contributes to COPD and suggests new precision therapies targeting this process.

Contribution

The paper introduces ferroptosis as a novel driver of COPD and proposes precision therapeutic strategies targeting the ferroptosis-immune axis.

Findings

Cigarette smoke induces mitochondrial fission and lipid peroxidation, promoting ferroptosis in airway cells.

Nrf2 dysfunction in macrophages may enhance iron retention and ferroptosis via ferritinophagy.

Plasma MDA levels correlate with COPD severity and lung function decline.

Abstract

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.

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