Dual role of IL-17A in COPD: amplifier of inflammatory cascades and mediator of airway remodeling and alveolar destruction

Corticosteroid resistance remains a central challenge in managing chronic obstructive pulmonary disease (COPD). This refractory phenotype is primarily driven by persistent, neutrophil-dominated airway inflammation. Interleukin-17A (IL-17A) bridges innate and adaptive immunity and helps sustain this refractory inflammation, although it operates within a redundant cytokine network and its pathogenic contribution is clearest in a defined molecular subset of patients. Following an overview of upstream drivers including lung-gut microbiome dysbiosis and Th17/Treg immune imbalance, the downstream effector network of IL-17A is analyzed. In sustaining inflammation, IL-17A stabilizes pro-inflammatory transcripts via ACT1-mediated post-transcriptional regulation and produces a self-amplifying positive feedback loop with neutrophil extracellular traps (NETs). In tissue remodeling, IL-17A induces alveolar epithelial ferroptosis via the ACT1-TRAF6-p38 MAPK cascade to drive emphysema. It also mediates irreversible structural alterations in the airway and alveolar parenchyma by inhibiting fibroblast autophagy through the PI3K/AKT/mTOR pathway and inducing epithelial mucus hypersecretion. Given the lack of significant clinical benefit from early non-selective IL-17A blockade in unselected populations, precision intervention strategies guided by clinical endotypes are evaluated. Optimizing next-generation targeted therapies in COPD necessitates biomarker-driven patient stratification, coupled with upstream signal interception and the restoration of systemic immune homeostasis. Together, these strategies support a shift from symptomatic management toward endotype-specific disease modification.