Metformin Modulates Systemic Lipid Remodeling after Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) induces systemic metabolic disturbances, particularly affecting lipid metabolism, which may contribute to secondary injury. Metformin has pleiotropic effects on mitochondrial function and lipid homeostasis, but its impact on the circulating lipidome after TBI remains poorly characterized. Methods: We performed plasma lipidomic profiling in a porcine TBI model with metformin or control pretreatment. Paired pre- and post-TBI samples from 20 swine enabled within-subject comparisons. Lipidomic data were analyzed using complementary univariate and multivariate approaches, including paired differential abundance testing, principal component analysis (PCA), unsupervised hierarchical clustering with permutation-based cluster purity assessment, and sparse partial least squares discriminant analysis (sPLS-DA). Results: Unsupervised analyses demonstrated coordinated lipidomic remodeling following TBI, characterized by enrichment of triglycerides and depletion of phosphatidylinositols. Metformin treatment had minimal effects on baseline metabolic profiles, with only subtle multivariate separation and near-chance classification performance. In contrast, post-TBI samples showed clearer treatment-associated differences, including improved separation in PCA, hierarchical clustering, and sPLS-DA models. These differences were driven by coordinated changes across multiple lipid classes rather than large shifts in individual metabolites. Notably, metformin treatment was associated with altered post-TBI patterns of triglycerides containing polyunsaturated fatty acids, phospholipids, lysophospholipids, and cholesteryl esters, suggesting modulation of injury-associated lipid remodeling. Conclusions: Metformin exerts modest effects on baseline lipid metabolism but is associated with coordinated alterations in the systemic lipidomic response following TBI. These findings support a context-dependent role for metformin as a modulator of post-injury metabolic remodeling and highlight lipid pathways as potential targets for therapeutic intervention after TBI.