Cuproptosis: The metabolic-immune axis in chronic obstructive pulmonary disease pathogenesis and therapeutics

Chronic Obstructive Pulmonary Disease (COPD) remains a leading cause of global morbidity and mortality, characterized by progressive airflow limitation and chronic inflammation that current therapies fail to effectively modify. The recent discovery of cuproptosis-a copper-dependent, regulated cell death mechanism driven by mitochondrial proteotoxic stress-provides a compelling framework to reinterpret COPD pathophysiology. In this review, we advance the hypothesis that cuproptosis functions not merely as a passive consequence but as a critical amplifier within a self-sustaining "Metabolic-Immune Cell Death Axis" that drives disease chronicity and progression. We synthesize evidence demonstrating that cigarette smoke actively disrupts pulmonary copper homeostasis, creating a microenvironment permissive for cuproptosis. Central to our model is a vicious cycle wherein cuproptotic death of structural cells releases immunogenic damage-associated molecular patterns (DAMPs) that fuel neutrophilic inflammation and pro-inflammatory macrophage polarization; in turn, this inflammatory milieu further impairs copper handling in surviving cells, sensitizing them to subsequent death. A key determinant of this process is cellular metabolic dependency-cells reliant on oxidative phosphorylation (such as alveolar type II epithelial cells and anti-inflammatory M2 macrophages) are predicted to be exquisitely vulnerable. Transitioning from mechanism to transitional potential, we survey cuproptosis-related biomarkers and emerging therapeutic strategies-including lung-targeted copper chelators, ionophores, nanoplatforms, and PROTAC-based sensitizers-while explicitly distinguishing established evidence from speculative hypotheses. Critically, we emphasize that all these approaches remain at preclinical or early exploratory stages, with no clinical trials yet conducted in COPD. By delineating a roadmap for future investigation-prioritizing direct human evidence, biomarker validation, and rigorous preclinical safety studies-we argue that the cuproptosis-immune axis warrants systematic exploration as a potential target for disease-modifying therapy, while acknowledging the substantial hurdles that must be overcome before clinical translation can be contemplated.