Novel biologic and molecular targets in COPD: Bridging precision medicine and lung regeneration

Chronic obstructive pulmonary disease (COPD) is no longer considered a homogeneous disorder, but rather a syndrome driven by diverse inflammatory and molecular endotypes. While inhaled therapies remain the cornerstone of treatment, many patients continue to experience exacerbations, progressive airflow limitation, and impaired quality of life. This state-of-the-art review synthesises current evidence on biologic and molecular therapeutics for COPD. Successes and failures of cytokine-targeted therapies, including interleukin-4 receptor alpha (IL4Ra), interleukin-5 and 5 receptor (IL-5/IL-5R), interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and C–X–C motif chemokine receptor 2 (CXCR2) antagonists, are critically appraised, and reasons for trial failure despite strong mechanistic rationale are explained. Novel concepts, including epithelial alarmin blockades, neutrophil extracellular trap (NET) suppression, small-molecule phosphodiesterase-3, 4 (PDE3/4) inhibitors, and molecular reversal of corticosteroid resistance, are summarised from a translational perspective. Beyond inflammation, the field is expanding towards lung regeneration through stem-cell-based therapies, exosomes, gene and RNA editing, and metabolic reprogramming of dysfunctional epithelium. Artificial intelligence, radiomics, multi-omics integration, and digital biomarkers promise individualised prediction of treatment response and early exacerbation detection, shifting COPD towards a ‘digital precision’ model.