Metabolic Reprogramming of Endothelial-Related Pathways in COVID-19 Patients Treated with Hyperbaric Oxygen Therapy: A Randomized Clinical Trial

COVID-19, caused by SARS-CoV-2, is increasingly recognized as a systemic disorder with inflammation, endothelial dysfunction, and metabolic perturbations. This study aimed to characterize metabolic changes in COVID-19 patients undergoing hyperbaric oxygen therapy (HBOT). The clinical trial was registered in EudraCT (2020-002722-90, 3 May 2020), prior to patient enrollment. Thirty hospitalized patients were randomized to HBOT (n=14) or standard care (n=14). The HBOT group received five sessions at 2.5 ATA for 75 minutes. Serum metabolites were analyzed using high-resolution LC-MS. Significant changes were observed in metabolites related to arginine/NO metabolism, creatine turnover, phospholipid remodeling, and pterin derivatives. Pathway analysis highlighted the urea cycle, glycerophospholipid remodeling, niacin metabolism, and folate/pterin pathways. HBOT patients showed enhanced metabolic network connectivity. The findings suggest that HBOT induces systemic metabolic adaptations involving amino acid and lipid pathways, as well as redox-related metabolites, which may intersect with vascular and inflammatory regulation.