Table 1.

Summary table of the potential metabolic driver mechanisms and how they may be involved in cancer.

Relevant Events		In Atherosclerosis	In Cancer
Oncogenic signals	PI3K–Akt–mTOR	Regulates key metabolic processes Regulates glycolysis, OXPHOS, autophagy Is activated in response to insulin to protect against mitogenic effects	Mediates the high demand for cellular nutrients in cancer cells Reprograms cellular metabolism and promotes glycolysis Increases autophagy through enhanced TFEB
	AMPK	Inhibits ROS and foam cell formation LKB1-AMPK activation inhibits fatty acid and cholesterol synthesis Improves insulin sensitivity	Either represses or promotes tumor growth depending on the context
	TLRs	TLR2, TLR4, and TLR9 are involved in endothelial dysfunction and atherosclerosis progression via the expression of inflammatory cytokines	Uncontrolled activation of TLR by chronic inflammatory stimulation with oxLDL, which may ultimately lead to the development of cancer HMGB1, a key ligand for TLRs, provokes inflammatory responses
	NLRP3 inflammasome	OxLDL activates NLRP3, recruits caspase, leading to formation of proatherogenic cytokines (IL-1β) and atheromatous plaque	Warrants further investigations of complicated and contradictory involvement in tumorigenesis Protective role in certain cancers has been shown TRPM2, a regulator of NLRP3, is overexpressed in many cancers
	Notch	DLL4-Notch1 controls the differentiation of macrophages into proinflammatory M1 type involved in the development of atherosclerosis	Associated with different types of cancer Can act as oncogene or tumor suppressor DLL4-Notch implicated in cell-to-cell signaling and angiogenesis in cancer
	Wnt	Controls lipid homeostasis and storage Aberrant Wnt signaling may be important in the pathogenesis of atherosclerosis	Aberrant activation is critical for primary transformation/metastasis Promotes EMT via crosstalk with TGF-β Activates PI3K/Akt, which stimulates HIF-1a-induced metabolic reprogramming
Angiogenic factors	VEGF/VEGFR	Complex and diverse effects VEGF-A may prevent the repair of endothelial damage, contributing to atherogenesis Dysregulation of VEGF-A/VEGFR-1-NRP1 signaling could inhibit chylomicron absorption Decreases the activity of LPL, resulting in accumulation of atherogenic lipoproteins VEGF-B has lipid-lowering effect and, via VEGFR-1/AMPK and NRP-1, controls the uptake of fatty acids by ECs VEGF-B impairs recycling of LDLRs, leading to reduced cholesterol uptake and decrease in GLUT1-dependent endothelial glucose uptake	VEGF/VEGFRs are upregulated in solid tumors, and they significantly contribute to formation of tumor blood vessels, leading to cancer development and dissemination
	Angiopoietins	Ang-1 may be proatherogenic Ang-2, an antagonist of ang-1, may inhibit atherosclerosis by limiting LDL oxidation	Ang-2 is extensively expressed in tumor endothelial cells and triggers tumor angiogenesis Ang-2 augments migration, invasion, and EMT in lung cancer
	NRF2	Considered an important defense mechanism against ASCVD Underlying mechanisms are barely known	Paradoxical roles in cancer, either acting as tumor suppressor or exerting oncogenic effects NRF2 regulates antioxidant response by eliminating ROS Maintains a normal redox state in cancer NRF2 activation, along with TIGAR, supports toxic ROS scavenging NRF2/KEAP1 may also protect against aberrant inflammation, which can result in cell damage and lead to malignant cell transformation
	HIF-1a	Exerts both detrimental and beneficial actions, depending on the cell type expressing HIF May contribute to endothelial cell dysfunction OxLDL induces HIF-1a expression HIF-1a expression depends on ROS	Key regulator in cancer metabolism, induces the switch from OXPHOS to permanent aerobic glycolysis Upregulates angiogenic factors
Lipogenic factors	OxLDL/LOX-1	OxLDL uptake by macrophages leads to foam cell formation and initiation of atherosclerotic plaques Binding of oxLDL to LOX-1 increases ROS LOX-1 mediates oxLDL-induced inflammation	May disrupt endothelial barrier Upregulates HIF-1a and miR-210 Downregulates SPRED2 associated with metastatic phenotypes Trigger factor for EMT Induces autophagy
	PCSK9	Regulates cholesterol metabolism Increases LDL Regulates adipogenesis, immune responses Interacts with LOX-1 and other receptors Increases TLR4 expression	PCSK9 is highly expressed and closely associated with incidence and progression of the majority of cancers
	SREBPs	May exacerbate the initiation and progression of atherosclerosis SREBP-1 activates the synthesis of fatty acids; SREBP-2 increases the synthesis of cholesterol SREBP2 activates NLRP3 in ECs SREBP regulates the expression of PCSK9 and increases miR-33a and miR-33b expression to facilitate lipid homeostasis	SREBPs are significantly upregulated in human cancers They mediate a mechanistic link between lipid metabolism reprogramming and malignancy PI3K/Akt/mTOR/SREBP1 promotes cholesterol uptake in cancer cells PI3K/Akt/mTOR/SREBP1 protects cancer cells from ferroptosis Not entirely clear whether lipid accumulation induced by microRNAs through SREBPs has a direct link to cancer cell phenotype SREBP2 upregulates mevalonate pathway, which is oncogenic
	FASN	Exogenous uptake and release of FFAs Acts as an oxLDL signal-transducing receptor Could induce insulin resistance and β-cell dysfunction	Associated with poor prognosis ROS-mediated FASN promotes lipid synthesis and tumor growth Activates oncogenic signaling like Wnt, promoting EMT and metastasis PI3K/Akt activation, via positive feedback, maintains high levels of FASN in cancer cells
	LXRs	Atheroprotective, promotes HDL biogenesis Upregulates ABCA1 TIGAR interferes with LXR expression Is associated with ASCVD	LXR activation may produce a strong anti-tumor response in mice May contribute to the development of colorectal cancer
	SCD1	Central regulator of lipid metabolism and fat storage Directly regulated by SREBPs and LXRs Catalyzes the generation of MUFAs to form new SFAs	Important role in promoting cancer cell proliferation and metastasis Inhibition reduces MUFA/SFA ratio Induces ferroptosis TIGAR induces ferroptosis resistance in colorectal cancer cells via ROS/AMPK/SCD1 signaling
	ACSS2	Important in lipid synthesis forms a complex with TFEB	Inversely correlates with overall survival in breast cancer Facilitates the adaptation of cancer cells in TME
Adipogenic factors	LDs	Involved in maintaining lipid homeostasis	Recognized as a key feature of cancer Release fatty acids to generate acyl-CoA In mitochondria, through fatty acid oxidation, produce energy to boost cancer cell proliferation and metastasis Synthesis of UPR in mitochondria regulates ROS defenses and metabolism and ensures redox balance Highly aggressive CSCs are abundant in LDs of some cancer types

Note: PI3K-Akt, phosphoinositide 3-kinase—protein kinase B; TFEB, endothelial transcription factor EB; OXPHOS, oxidative phosphorylation; AMPK, adenosine monophosphate-activated protein kinase; TLRs, toll-like receptors; NLRP3, Nod-like receptor protein 3 inflammasome; HMGB1, high-mobility group box 1; TRPM2, transient receptor potential melastatin 2; TGF-β, transforming growth factor-β; VEGF/VEGFRs, endothelial growth factor/VEGF receptors; NRF2, nuclear factor erythroid 2-related factor 2; HIF-1a, hypoxia-inducible factor-1a; oxLDL, oxidized LDL; LOX-1, Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1; SREBPs, sterol regulatory element-binding proteins; FASN, fatty acid synthase; LXRs, liver X receptors; SCD, stearoyl-CoA desaturase; ACSS2, acetyl-CoA synthetase 2; LPL, plasma lipoprotein lipase; ECs, endothelial cells; LDLR, low-density lipoprotein receptor; NRP1, Neuropilin 1; GLUT1, glucose transporter 1; EMT, epithelial–mesenchymal transition; TIGAR, TP53-induced glycolysis and apoptosis regulator; KEAP1, Kelch-like ECH-associated protein 1; SPRED2, sprout-related EVH1 domain 2; LOX-1, Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1; SREBPs, Sterol regulatory element-binding proteins; miR, microRNA; FFAs, free fatty acids; HDL, high-density lipoprotein; ABCA1, ATP-binding cassette subfamily A member 1; MUFAs, monounsaturated fatty acids; SFA, saturated fatty acid; TME, tumor microenvironment; LDs, lipid droplets; acyl-CoA, acyl-CoA synthetase; UPR, unfolded proteins; CSCs, cancer stem cells.