Enríquez Rodríguez, César JesséAgranovich, BellaPascual Guàrdia, Sergi, 1979-Faner, RosaCamps-Ubach, RamonCastro-Acosta, Ady AngélicaLopez-Campos, Jose LuisPeces-Barba Romero, GermánSeijó Maceiras, LuisCaguana Vélez, Oswaldo AntonioRodriguez-Chiaradia, Diego AgustínBarreiro Portela, EstherMonsó Molas, EduardCosío, Borja G.Abramovich, IfatAgustí, AlvarCasadevall Fusté, CarmeGea Guiral, Joaquim2025-09-092025-09-092025Enríquez-Rodríguez CJ, Agranovich B, Pascual-Guàrdia S, Faner R, Camps-Ubach R, Castro-Acosta A, et al. Metabolomic signatures predict seven-year mortality in clinically stable COPD patients. Int J Mol Sci. 2025 Jul 1;26(13):6373. DOI: 10.3390/ijms261363731422-0067http://hdl.handle.net/10230/71162Chronic Obstructive Pulmonary Disease (COPD) is a complex condition with high mortality. Early identification of patients at increased risk of death remains a major clinical challenge. This pilot study aimed to explore whether plasma metabolomic profiling could aid in the prediction of long-term (7-year) mortality and provide insight into potential underlying mechanisms. Plasma samples from 54 randomly selected stable COPD patients were analyzed using both untargeted and semi-targeted LC-MS approaches. After excluding patients with unclear death data, non-COPD-related deaths and metabolomic outliers, 41 individuals were included in the final analysis. During follow-up, 13 patients (32%) died, and 28 survived. Univariate analysis identified 12 metabolites—mainly amino acids—that differed significantly between the two groups. Functional analysis suggested a significant disruption in energy production pathways. Predictive models developed using machine learning algorithms, consisting of either ten metabolites alone or nine metabolites plus FEV1, achieved high accuracy for 7-year mortality prediction, with the latter model performing slightly better. Internal validation was conducted using five-fold cross-validation. While exploratory, these findings support the hypothesis that early metabolic alterations, particularly in energy pathways, may contribute to long-term mortality risk in stable COPD patients, and could complement traditional prognostic markers such as FEV1.application/pdfeng© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ijms26136373COPDMortalityMetabolomicsEnergyAmino acidsRedoxMicrobiotainfo:eu-repo/semantics/openAccess