Regulated cell death in COPD: Modulators, crosstalk mechanisms, and therapeutic opportunities

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disorder, with emerging evidence highlighting the central role of regulated cell death (RCD) in its pathogenesis. However, the regulatory mechanisms, crosstalk between different RCD pathways, and their role in intercellular communication remain poorly understood. This review examines major forms of RCD (apoptosis, necroptosis, ferroptosis, pyroptosis, NETosis, and PANoptosis) in COPD, exploring their regulation, crosstalk, role in intercellular signaling, and potential as therapeutic targets. Mechanistically, RCD is regulated through membrane receptors, epigenetic modifications, and post-translational processes. Endoplasmic reticulum (ER) stress, reactive oxygen species, and autophagy serve as common nodes across multiple RCD types. Excessive ER stress triggers apoptosis, while impaired autophagy promotes oxidative stress, cellular senescence, and inflammation. Conversely, excessive autophagy-including mitophagy, ferritinophagy, lysosomal autophagy, ER-phagy, and chaperone-mediated autophagy-can induce apoptosis, necroptosis, and ferroptosis. Regarding inter-pathway crosstalk and RCD-mediated intercellular communication: reduced macrophage apoptosis exacerbates epithelial inflammation and apoptosis; macrophage inflammation or ferroptosis can further promote epithelial ferroptosis or inflammatory responses. Ferroptosis in airway epithelial cells aggravates their own pyroptosis, and pyroptotic epithelial cells secrete exosomes that induce macrophage pyroptosis. NETotic neutrophils release extracellular DNA, driving inflammation in airway epithelia. Therapeutically, current exploratory strategies target these death pathways through diverse approaches, including existing pharmaceuticals, hormones, phytochemicals, recombinant proteins and nucleic acids, stem cell and regenerative therapies, and modulation of the airway microbiome. Deciphering the RCD network in COPD not only enhances our understanding of disease heterogeneity but also paves the way for developing precision therapeutics.