Endothelial-to-mesenchymal transition in atherosclerosis: mechanisms, therapeutic targets, and future perspectives

Endothelial-to-mesenchymal transition (EndMT) is an endothelial plasticity program that contributes to vascular remodeling, inflammation, extracellular matrix remodeling, calcification, and plaque instability in atherosclerosis. Recent lineage-tracing, single-cell RNA sequencing, and spatial transcriptomic studies have revealed that EndMT is not a uniform or irreversible process, but rather a spectrum of partial, intermediate, and advanced endothelial transition states with stage- and region-specific effects. During atherosclerosis, EndMT may participate in lesion initiation, plaque progression, fibrous cap remodeling, and advanced plaque vulnerability. Mechanistically, EndMT is regulated by interconnected metabolic, signaling, transcriptional, epigenetic, and biomechanical pathways, including TGF-β/SMAD, FGF/FGFR1, BMP, Notch, Wnt/β-catenin, KLF2/KLF4, glycolysis-lactate-lactylation, fatty acid oxidation, HDACs, non-coding RNAs, and extracellular vesicle-mediated communication. Therapeutically, EndMT-targeted strategies should aim to prevent or reverse early maladaptive EndMT while selectively restraining sustained inflammatory, osteogenic, fibroblast-like, or matrix-degrading EndMT states. However, clinical translation remains limited by marker nonspecificity, vascular-bed heterogeneity, disease-stage dependence, inadequate modeling of human plaque rupture, and the lack of validated biomarkers. Future integration of lineage tracing, single-cell and spatial multi-omics, human-relevant models, plaque-risk stratification, and targeted delivery systems may enable precise modulation of EndMT to slow atherosclerosis progression and improve plaque stability.