Atherosclerosis (AS), a major global health issue, results from endothelial dysfunction and reprogramming, including Endothelial-To-Mesenchymal Transition (EndMT), endothelial-to-immune cell-like transition (EndICLT), and metabolic remodeling. This review elucidates these mechanisms, focusing on the TGF-β/Smad, Wnt/β-catenin, and Notch pathways that drive endothelial plasticity and plaque instability. Oxidised low-density lipoprotein (ox-LDL) induces EndMT through the LOX-1/NF-κB pathway and snail stabilisation; meanwhile, HIF-1α activation increases glycolysis and lactate production, promoting inflammation. Disordered blood flow exacerbates these effects through mitochondrial impairment of oxidative phosphorylation and induction of EndICLT, thereby enhancing the recruitment of immune cells. Statins are less than perfect in lowering LDL-C and have some side effects; therefore, new methods need to be found. Targeting endothelial reprogramming with small-molecule inhibitors (e.g., PIM447®), natural compounds (e.g., ginsenoside Rb1®), and Extracellular Vesicles (EVs) delivering miR-126-3p to alleviate EndMT, EndICLT, and metabolic dysfunction, stabilising plaques. In the future, research needs to focus on developing biomarkers, precise delivery (such as CRISPR-Cas9), and multi-pathway therapies to achieve all-round management of AS. This review provides a reference for precise therapies of refractory vascular diseases via endothelial reprogramming.
Xiao et al. (Wed,) studied this question.