Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities Atherosclerotic cardiovascular disease (ASCVD) is a chronic, non-resolving inflammation driven by the accumulation of ApoB-containing lipoproteins. Recent research highlights the role of metabolic dysregulation in the progression of atherosclerosis, including imbalances in lipid metabolism, glucose utilization, and amino acid metabolism. These dysregulations lead to pro-atherogenic responses through complex interactions between endothelial cells (ECs), vascular smooth muscle cells (vSMCs), and immune cells. Despite optimal lipid-lowering treatments, ASCVD remains a leading cause of morbidity and mortality worldwide. This review summarizes recent advances in understanding the role of metabolic dysregulation in atherosclerosis, explores the complexity of metabolic cross-talk between lesional cells, and highlights emerging technologies that may illuminate unknown aspects of metabolism in atherosclerosis. It also suggests strategies for targeting these metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas. ECs play a critical role in atherosclerosis by responding to disturbed fluid shear stress (FSS), which drives EC activation, increased inflammatory gene expression, and paracellular permeability. ApoB-containing lipoproteins accumulate in areas of paracellular pores or are transported across ECs via transcytosis. These lipoproteins are retained in the subendothelial matrix, where they undergo modifications that lead to the formation of foam cells. Foam cells compromise their beneficial immune functions and enhance their susceptibility to cell death. EC metabolism is influenced by mechanical forces and FSS. Disturbed FSS promotes aerobic glycolysis, which modulates mechanosensitive YAP/TAZ complex activation, perpetuating glycolysis. Conversely, unilaminar FSS induces the transcription factors KLF2 and KLF4, which prevent atherosclerosis by driving the expression of eNOS and inducing thrombomodulin. Unilaminar FSS also stimulates mitochondrial oxidative phosphorylation, leading to increased reactive oxygen species production, which initiates mitophagy and scaffolds the ERK5 signalling axis to amplify KLF2-mediated eNOS expression. vSMCs contribute to plaque stability by forming the collagen-rich fibrous cap. They can dedifferentiate and acquire genes resembling myofibroblasts and macrophages. vSMCs also contribute to vascular calcification due to their transition to chondrocyte-like and osteoblast-like cells. Cellular metabolism guides phenotypic modulation of vSMCs, with glucose utilization controlling vSMC dedifferentiation. Metabolic reprogramming towards glycolysis is critical for vSMC dedifferentiation during atherosclerosis. The mammalian target of rapamycin complex 1 (mTORC1) is a pivotal regulator of vSMC phenotypic modulation. Macrophage immunometabolism is crucial in atherosclerosis,Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities Atherosclerotic cardiovascular disease (ASCVD) is a chronic, non-resolving inflammation driven by the accumulation of ApoB-containing lipoproteins. Recent research highlights the role of metabolic dysregulation in the progression of atherosclerosis, including imbalances in lipid metabolism, glucose utilization, and amino acid metabolism. These dysregulations lead to pro-atherogenic responses through complex interactions between endothelial cells (ECs), vascular smooth muscle cells (vSMCs), and immune cells. Despite optimal lipid-lowering treatments, ASCVD remains a leading cause of morbidity and mortality worldwide. This review summarizes recent advances in understanding the role of metabolic dysregulation in atherosclerosis, explores the complexity of metabolic cross-talk between lesional cells, and highlights emerging technologies that may illuminate unknown aspects of metabolism in atherosclerosis. It also suggests strategies for targeting these metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas. ECs play a critical role in atherosclerosis by responding to disturbed fluid shear stress (FSS), which drives EC activation, increased inflammatory gene expression, and paracellular permeability. ApoB-containing lipoproteins accumulate in areas of paracellular pores or are transported across ECs via transcytosis. These lipoproteins are retained in the subendothelial matrix, where they undergo modifications that lead to the formation of foam cells. Foam cells compromise their beneficial immune functions and enhance their susceptibility to cell death. EC metabolism is influenced by mechanical forces and FSS. Disturbed FSS promotes aerobic glycolysis, which modulates mechanosensitive YAP/TAZ complex activation, perpetuating glycolysis. Conversely, unilaminar FSS induces the transcription factors KLF2 and KLF4, which prevent atherosclerosis by driving the expression of eNOS and inducing thrombomodulin. Unilaminar FSS also stimulates mitochondrial oxidative phosphorylation, leading to increased reactive oxygen species production, which initiates mitophagy and scaffolds the ERK5 signalling axis to amplify KLF2-mediated eNOS expression. vSMCs contribute to plaque stability by forming the collagen-rich fibrous cap. They can dedifferentiate and acquire genes resembling myofibroblasts and macrophages. vSMCs also contribute to vascular calcification due to their transition to chondrocyte-like and osteoblast-like cells. Cellular metabolism guides phenotypic modulation of vSMCs, with glucose utilization controlling vSMC dedifferentiation. Metabolic reprogramming towards glycolysis is critical for vSMC dedifferentiation during atherosclerosis. The mammalian target of rapamycin complex 1 (mTORC1) is a pivotal regulator of vSMC phenotypic modulation. Macrophage immunometabolism is crucial in atherosclerosis,