Exercise and Epigenetic Regulation in COPD: Current Evidence and Potential Mechanistic Pathways.

Chronic obstructive pulmonary disease (COPD) remains a major global health burden, characterized by persistent airflow limitation, progressive lung tissue destruction, and systemic comorbidities. Conventional pharmacological therapies alleviate symptoms but have limited efficacy in halting disease progression. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, are increasingly recognized as important regulators of the inflammatory and oxidative pathways involved in COPD pathogenesis. Exercise is a cornerstone of pulmonary rehabilitation and consistently improves exercise capacity, symptoms, and systemic inflammatory markers in COPD. Emerging studies suggest that exercise is associated with changes in epigenetic regulators. This review summarizes current clinical and preclinical findings on how aerobic training, resistance exercise, and high-intensity interval training are linked to alterations in DNA methylation, histone marks, and non-coding RNA expression, and discusses the biological plausibility that these changes could influence COPD-related pathways such as antioxidant responses, protease and antiprotease balance, and inflammatory signaling. Critical gaps remain regarding tissue specificity, temporal dynamics, and causal mechanisms. Future research should prioritize longitudinal and mechanistic studies to clarify whether epigenetic responses contribute to the benefits of exercise in COPD and to assess their potential as biomarkers or therapeutic targets.