Alteration of Lipid Metabolism in Patients with IPF and Its Association with Disease Severity and Prognosis: A Case–Control Study

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves complex interactions between epithelial, mesenchymal, immune, and endothelial cells, often aggravated by lipid metabolism dysfunction, mitochondrial, and peroxisomal abnormalities. Changes in lipid metabolism may drive fibrotic processes, suggesting the potential of lipid biomarkers for disease monitoring. We compared here the cholesterol metabolism and very-long-chain fatty acid profiles of patients with IPF with healthy controls. The IPF patients' lipidic profiles were also evaluated according to disease severity and progression rate. This prospective, observational study involved 50 IPF patients at disease diagnosis before antifibrotic treatment initiation and 50 age- and gender-matched healthy controls. Using a serum lipidomic profile, we focused on cholesterol synthesis, mitochondrial and peroxisomal markers, inflammatory lipids, and oxidative stress markers. Disease severity was evaluated using the Gender-Age-Physiology (GAP) index, while the prognosis was assessed by classifying patients as rapid or slow progressors based on a 24-month follow-up. IPF patients exhibited lower levels of cholesterol synthesis precursors (e.g., lathosterol), mitochondrial oxysterols, and inflammatory mediators (e.g., arachidonic acid) compared to controls. Reduced levels of these biomarkers were also associated with higher disease severity and rapid disease progression. Conversely, some peroxisomal markers (e.g., brassidic acid and nervonic acid) showed altered trends depending on disease severity. Our findings indicate that patients with IPF, compared to healthy controls, may show lipidomic alterations, particularly a reduction in cholesterol precursors and docosahexaenoic acids, which are also associated with IPF severity and progression. While preliminary, this study suggests lipidomics to be a promising tool to stratify IPF severity and prognosis.