Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder with rising global morbidity and mortality. Emerging evidence suggests that systemic metabolic alterations, particularly dyslipidemia, contribute to COPD pathogenesis. However, the mechanisms linking lipid dysregulation to pulmonary inflammation and tissue injury remain poorly defined. METHODS: Untargeted metabolomic profiling was performed on plasma samples from healthy individuals and patients with stage III-IV COPD to identify disease associated metabolic alterations. A high-cholesterol diet (HCD) mouse model, with or without chronic cigarette smoke exposure, was used to examine the impact of systemic cholesterol elevation on lung structure and inflammation. THP-1 derived and bone marrow derived macrophages were employed to assess cholesterol-induced mitochondrial dysfunction, ROS production, and downstream inflammatory signaling. Transcriptomic profiling was conducted to identify key molecular mediators. RESULTS: Plasma metabolomics revealed significant dysregulation of lipid pathways in COPD, with elevated cholesterol levels inversely correlated with lung function. In vivo, HCD feeding induced pulmonary inflammation and further exacerbated cigarette smoke induced alveolar destruction. In macrophages, combined cholesterol loading and cigarette smoke extraction treatment disrupted mitochondrial integrity, reduced respiratory capacity, and increased ROS production. Excess ROS upregulated PPIA, which activated NF-κB signaling and enhanced IL-1β secretion. Silencing PPIA or inhibiting ROS attenuated NF-κB activation and cytokine release. Consistent with these findings, lungs from HCD-fed, cigarette smoke exposed mice exhibited increased PPIA expression and NF-κB phosphorylation, and PPIA levels were elevated in bronchoalveolar lavage fluid from COPD patients. CONCLUSIONS: This study identifies a cholesterol-driven metabolic–inflammatory pathway in which mitochondrial dysfunction and ROS-dependent activation of the PPIA–NF-κB axis in macrophages contribute to persistent pulmonary inflammation in COPD. These findings establish a mechanistic link between systemic cholesterol dysregulation and COPD progression and highlight cholesterol metabolism and mitochondrial homeostasis as potential therapeutic targets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-025-01591-w.