# 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.

## Key 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.