Chronic Obstructive pulmonary disease (COPD) is an inflammatory lung disorder affecting approximately 10% of the adult population and is currently the third leading cause of death worldwide. It is characterized by poorly reversible airflow limitation resulting from chronic airway inflammation and airway remodeling, as well as reduced elastic recoil (emphysema). Despite advances in bronchodilation and anti-inflammatory therapy, few interventions to date have convincingly modified the natural history of the disease [1].

Patients with COPD exhibit a complex airway inflammatory response, including neutrophilic inflammation, eosinophil-associated inflammation, or the coexistence of mixed inflammatory endotypes. Among these, neutrophilic inflammation has been associated with disease severity and clinical progression. An increased number of dysfunctional neutrophils, together with elevated levels of neutrophil-related cytokines and chemokines, contributes to persistent airway inflammation and tissue injury [2]. Activated neutrophils release high concentrations of active neutrophil serine proteases (NSPs), including neutrophil elastase (NE), cathepsin G (CatG), and proteinase 3 (PR3), which may play a central role in COPD pathobiology. Excessive NSP activity promotes a protease-antiprotease imbalance, leading to airway wall thickening, luminal narrowing, alveolar destruction (emphysema), increased mucus hypersecretion, and the formation of neutrophil extracellular traps (NETs). These processes impair mucociliary clearance and increase susceptibility to infection [2–4]. Consistent with this biological role, increased NSP activity has been associated with worse clinical outcomes in COPD, including disease severity, as assessed by GOLD stage, and lung function decline [3,4]. In other neutrophilic airway diseases, such as bronchiectasis, increased NSP activity has been associated with increased exacerbation risk, greater symptom burden, lung function decline, and mortality [5].

Dipeptidyl peptidase-1 (DPP-1), also known as cathepsin C, is the enzyme responsible for the activation of NSPs, including NE, CatG, and PR3, during neutrophil maturation in the bone marrow. DPP-1 is essential for converting inactive zymogens of these proteases into their active forms [6]. Therefore, DPP-1 inhibition represents a novel therapeutic mechanism for broadly reducing NSP activity. Selective DPP-1 inhibition offers a novel anti-inflammatory and antiprotease strategy that may attenuate protease-mediated airway injury while preserving essential neutrophil functions, including chemotaxis, phagocytosis, and microbial killing [6]. This approach differs from strategies aimed at inhibiting neutrophil recruitment to the lung, which have long raised concerns regarding infection risk. Supporting the biological plausibility and safety of this strategy, Papillon-Lefèvre syndrome, a rare autosomal recessive genetic disorder caused by loss-of-function mutations in the DPP-1 gene, is characterized by a marked reduction in NSP activity without severe immunodeficiency. Palmoplantar hyperkeratosis and periodontitis are potential adverse effects that should be monitored [7]. Taken together, these observations support further evaluation of DPP-1 inhibition as a potential therapeutic approach in COPD, although these findings should be confirmed in future COPD studies.

Currently, the most robust clinical evidence supporting the therapeutic use of DPP-1 inhibitors comes from studies in bronchiectasis [5,8]. Brensocatib, the first DPP-1 inhibitor approved for clinical use, has consistently demonstrated an ability to reduce exacerbation frequency, increase time to first exacerbation, and improve patient-reported outcomes in patients with bronchiectasis in phase 2 and phase 3 clinical trials [9,10]. In addition, two other DPP-1 inhibitors, BI 1291583 and HSK31858, have demonstrated similar clinical effects, showing dose-dependent reductions in exacerbation frequency in phase 2 studies [11,12]. Importantly, the incidence of adverse events across these trials was very low, with only a higher incidence of mild hyperkeratosis and gingivitis/periodontitis observed among patients receiving DPP-1 inhibitor treatment. In addition, immunomodulatory effects of brensocatib were recently reported by Johnson et al. [13], including reduced airway mucin 5AC (MUC5AC) levels and increases in up to 15 cytokines/chemokines and antimicrobial peptides, such as secretory leukocyte protease inhibitor and α-defensin, supporting a potential effect on improved mucociliary clearance and pulmonary host defenses [14]. These studies have demonstrated safety and mechanistic confirmation in bronchiectasis. However, this evidence is still required in COPD, as several key questions remain unanswered.

First, which patients with COPD would benefit most from treatment? Insights from bronchiectasis may help inform patient selection in COPD. Most bronchiectasis trials have focused on the frequent-exacerbator phenotype, which is consistently associated with worse outcomes, as in COPD [14]. Other clinical features, including chronic bronchitis, airway bacterial infection, symptom burden, and/or sputum purulence, are also independently related to exacerbation risk and poorer outcomes in bronchiectasis and should also be considered in patients with COPD [15]. These characteristics, as well as coexisting bronchiectasis, may help define subgroups of patients with COPD who have strong neutrophilic and protease-driven inflammation and who therefore represent the most biologically plausible candidates for DPP-1 inhibition. The inclusion of such features in future COPD trial designs may help reduce heterogeneity in the target population.

Second, when should these patients be treated? Considering COPD as an inflammatory disease, a paradigm shift toward early intervention to prevent irreversible damage may be considered. The clinical effects observed in bronchiectasis and the reduction in MUC5AC expression raise the possibility that DPP-1 inhibitors may modify disease progression if introduced earlier, although robust evidence in COPD is still needed.

Overall, these observations support careful consideration of DPP-1 inhibition beyond bronchiectasis. Potential effects of DPP-1 inhibitors include reduced mucus hypersecretion, enhanced airway host defense, and limited tissue destruction. Potential candidates for this approach may include patients with COPD who have frequent exacerbations, chronic bronchitis, sputum purulence, and/or high NSP activity (Fig. 1). In these patients, DPP-1 inhibition could represent a targeted strategy to reduce protease-mediated lung injury. However, a precision-medicine approach will require prospective, phenotype-driven randomized clinical trials and validated tools to identify the relevant biological endotype.

Fig. 1.

Potential effects of DPP-1 inhibition in patients with COPD. CatG, cathepsin G; COPD, chronic obstructive pulmonary disease; DPP-1, dipeptidyl peptidase-1; NE, neutrophil elastase; NSPs, neutrophil serine proteases; PR3, proteinase 3.

In conclusion, the evidence on DPP-1 inhibitors in bronchiectasis is strong but should be considered supportive and indirect for COPD, because efficacy, safety, and patient selection remain to be established in COPD-specific studies. By targeting NSP activation upstream, these agents offer a mechanistically distinct approach that may complement existing anti-inflammatory and bronchodilator therapies, particularly in carefully selected patients with COPD and neutrophil-driven disease phenotypes. Nonetheless, several key uncertainties remain, including the identification of COPD subgroups most likely to benefit from this intervention, the optimal biomarkers to guide patient selection, such as NSP activity, sputum inflammatory profiles, or mucus-related traits, and the long-term safety of sustained protease modulation. Collectively, DPP-1 inhibition is a promising and biologically plausible strategy in COPD, but its future role depends on confirmation in randomized clinical trials specific to COPD and improved biological stratification of candidate patients.