Trained Immunity-Like Memory in Vascular Structural Cells: Metabolic-Epigenetic Reprogramming as a Driving Mechanism...

Despite major advances in lipid-lowering therapies and widespread achievement of optimal LDL-C targets, a substantial burden of residual cardiovascular risk (RCVR) persists, underscoring fundamental gaps in current preventive strategies. Existing mechanistic frameworks have largely centered on professional immune cells as the primary drivers of chronic vascular inflammation, insufficiently accounting for the durability and tissue specificity of vascular pathology after risk factor correction. Emerging evidence supports a paradigm in which vascular structural cells (VSCs), notably endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), acquire a trained immunity-like state that enables them to act as a long-term reservoir of pathogenic molecular memory. Repeated metabolic, inflammatory, or mechanical priming induces persistent phenotypic switching in VSCs through a tightly coupled metabolic-epigenetic axis. This process is characterized by PFKFB3-driven glycolytic reprogramming, rewired mitochondrial metabolism with accumulation of tricarboxylic acid cycle intermediates such as succinate and fumarate, and the establishment of stable epigenetic scars, including H3K4me1, H3K27ac, and histone lactylation. These epigenetic imprints lower activation thresholds and sustain exaggerated inflammatory and proliferative responses, providing a mechanistic basis for chronic vascular remodeling in clinical entities such as in-stent restenosis and cardiac allograft vasculopathy. Targeting vascular molecular memory by erasing maladaptive epigenetic programs, using bromodomain and extraterminal domain inhibitors or metabolic modulators such as metformin, represents a promising therapeutic avenue to mitigate RCVR beyond conventional lipid-centric approaches.