Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and chronic obstructive pulmonary disease (COPD) are frequently comorbid, affecting up to 41% of COPD patients. Both conditions exhibit significant metabolic and inflammatory dysregulation. While exercise training improves individual disease outcomes by reducing systemic inflammation, its therapeutic effects and underlying mechanisms in COPD patients with NAFLD comorbidity are not well understood. This pilot trial aimed to evaluate the impact of exercise on COPD patients with and without NAFLD, identifying potential biomarkers of exercise-induced regulation. METHODS: COPD patients, categorized by NAFLD status, participated in a 12-week exercise training program. Rehabilitation efficacy was assessed based on lung function and cardiopulmonary exercise test. Metabolic improvements were tested by measuring inflammatory factors, anti-inflammatory factors, etc., using ELISA and PCR methods. Transcriptomic analysis was performed on patients' samples before and after exercise, integrating external datasets to identify key molecular changes affecting both liver function and systemic inflammation. Hub genes were selected through bioinformatics analysis and validated for their expression in patient samples. RESULTS: Exercise training elicited beneficial adaptations in both groups. Notably, the COPD with NAFLD group exhibited a greater improvement trend in circulatory function and respiratory metabolic rate compared to COPD-only patients. However, the difference did not reach statistical significance (p > 0.05). Furthermore, post-exercise analysis indicated a more pronounced anti-inflammatory shift in the COPD+NAFLD group, with broader reductions in pro-inflammatory cytokines and upregulation of IL-4 compared to the COPD-only group. Transcriptomic analysis integrated with public datasets identified Early Growth Response 1 (EGR1) as a key exercise-response hub gene; its expression was downregulated in the COPD+NAFLD group after exercise but upregulated in the COPD-only group, correlating positively with M2 macrophages (derived from liver single-cell transcriptomic data) and negatively with monocytes. CONCLUSION: Our preliminary findings suggest that exercise training may offer unique benefits for patients with comorbid COPD and NAFLD, particularly by enhancing metabolic efficiency and circulatory function. EGR1 may serve as a potential biomarker for exercise responsiveness in this population, reflecting underlying immunomodulatory mechanisms. This insight may also aid in distinguishing COPD subtypes and tailoring exercise-based therapeutic strategies.