Angiogenesis is a normal physiological mechanism defined as the formation of new blood vessels and capillaries from already existing ones; this condition is called “sprouting” [174]. The angiogenic front of the sprouting vessel is characterized by two EC phenotypes, stalk and tip ECs, but the key event in sprouting angiogenesis is the selection of motile leading-edge tip cells [25,36]. Poorly perfused ECs exposed to high VEGF concentrations extend numerous filopodia and become tip cells, initiating sprouting angiogenesis. The degradation of the basal membrane and the detachment of mural cells then result in stalk cells [69]. While angiogenesis is considered an important mechanism for the development of atherosclerotic disease [25], it also represents one key event in several types of cancer [175]. This is because cancer is associated with a highly hypoxic state, which promotes hypoxic-tumor-derived transcription factors [176,177,178]. The most widely known angiogenic factors are the family of vascular endothelial growth factors (VEGF-A, VEGF-B), VEGF receptors (VEGFRs), and angiopoietins [179]. Other factors that promote angiogenesis and tumor expansion include HIF-1a (hypoxia-inducible factor-1a) and nuclear factor erythroid 2-related factor 2 (NRF2) [180]. The imbalance between angiogenic and antiangiogenic factors promotes an “angiogenic switch”, triggering blood vessel formation and angiogenesis [36].

Endothelial growth factor (VEGF) promotes the proliferation, migration, and spread of endothelial cells and is an undisputed crucial player in EC activation for both physiological and pathological angiogenesis [36,181,182]. VEGF triggers cell responses by recruiting the tyrosine kinase receptors VEGFR1/Flt-1, VEGFR2/KDR/Flk1, and VEGFR3/Flt-4, and among them, VEGFR2 is the most potent mediator of changes that occur during VEGF-induced tip cell selection [69].

The activation of the VEGF receptor by its ligand promotes signaling pathways important to endothelial cell proliferation, including phosphoinositide-3-kinase (PI3K), protein kinase B (PKB/Akt), and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway (p38-MAPK/ERK1/2), facilitating the migration of inflammatory cells and the release of inflammatory cytokines and proteolytic enzymes into the extracellular matrix (ECM) [183,184]. Moreover, under hypoxic stress, DLL4-NOTCH reacts and represses VEGFA-VEGFR2 signaling, inhibiting their differentiation into tip cells [69,152].

Important cell receptors for VEGF/VEGFR signaling in angiogenesis include TFEB and Neuropilin 1 (NRP1). TFEB relies on the catalytic activity of VEGF receptor 2 (VEGFR2) to regulate EC proliferation [185,186]. Vascular NRP1, as a receptor, participates in distinct types of signaling pathways that control cell migration in angiogenesis and has been shown to synergize with VEGF-A as a co-receptor for VEGFR2 [183,187,188].

VEGF is part of the classical angiogenic factors that mediate atherosclerotic angiogenesis, in addition to its role in neovascularization, plaque growth/progression, and instability [25]. VEGF has a multifactorial influence on energy homeostasis, the lipidemic profile, insulin resistance, glucose sensitivity, and cardiac function [189]. The effects of VEGFs on the development of atherosclerosis are complex and diverse, but VEGF-A prevents the repair of endothelial damage, contributing to atherogenesis and promoting monocyte adhesion, transendothelial migration, and activation [188]. VEGF-A, as part of the VEGF-A/VEGFR-1-NRP1 signaling pathway, regulates chylomicrons entering the chylous duct; thus, dysregulation could cause the inhibition of chylomicron absorption [190]. Also, VEGF-A decreases the activity of plasma lipoprotein lipase (LPL), resulting in the accumulation of triglycerides in chylomicrons and very low-density lipoproteins, which results in atherosclerosis promotion [191]. On the other hand, VEGF-B is known for its lipid-lowering effect. Acting via VEGFR-1/AMPK and NRP-1, VEGF-B regulates the transcription of vascular fatty acid transporters, thus controlling the uptake of fatty acids from circulating lipids by ECs and their further transcytosis, followed by lipid utilization in mitochondria [192]. In addition, VEGF-B signaling impairs the recycling of low-density lipoprotein receptors (LDLRs) to the plasma membrane, leading to reduced cholesterol uptake and membrane cholesterol loading, which also leads to a decrease in glucose transporter 1 (GLUT1)-dependent endothelial glucose uptake [193].

The expression of VEGF and VEGFRs is upregulated in solid tumors, and this significantly contributes to the formation of tumor blood vessels, leading to cancer development and dissemination [194]. Following the discovery that many tumors secrete VEGF, it is not unexpected that the VEGF pathway has been considered one of the most attractive targets for the development of antiangiogenic drugs [195]. The clinical benefit of drugs targeting the VEGF/VEGFR pathway, neutralizing monoclonal antibodies, has been modest for most tumor types; nevertheless, combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers have attained new interest [36,196].

Angiopoietins consist of a small group of secreted glycoproteins that are implicated not only in the normal process of angiogenesis, regulating vascular permeability and the growth, modification, and recovery of the blood vessels, but also in pathological vascular remodeling during inflammation, tumor angiogenesis, and metastasis [36,197]. In humans, angiopoietins constitute a small group of three secreted glycoproteins named Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), and Angiopoietin-4 (Ang-4) (the mouse ortholog is named Ang-3), which are ligands of the Tie-2 tyrosine kinase receptor [198]. Ang-1 is regarded as a strong Tie-2 agonist and promotes vessel maturation and survival through Tie-2 receptor phosphorylation and via the PI3K-Akt-mediated signaling pathway [83]. Ang-2 has been regarded as an antagonist of Tie-2 that competitively restrains Ang-1 binding. However, more recent studies imply that Ang-2 has a dual impact on angiogenesis since it acts either as a weak Tie-2 agonist or as a Tie-2 antagonist [36,199].

Angiopoietin-1 may play a proatherogenic role, while angiopoietin-2, which acts as an antagonist of Angiopoietin-1, may inhibit atherosclerosis by limiting LDL oxidation [200]. In line with this remark, in hypercholesterolemic LDLR−/−Apolipoprotein B (ApoB)100/100 mice, anti-angiopoietin-2-blocking antibodies exerted an anti-atherogenic effect [201]. Moreover, in mice, Ang-2 showed increased expression in lesions with intraplaque hemorrhage compared to regions of the lesions without [202]. From other experiments in mice, when Ang-4 protein was injected twice a week into atherosclerotic ApoE−/−mice, Ang-4 reduced atherosclerotic plaque size and vascular inflammation and inhibited atherogenesis [203]. Another study showed that genetic ablation of Ang-4 in adipose tissue results in enhanced plasma lipoprotein lipase (LPL) activity, the rapid clearance of circulating triacylglycerols, increased lipolysis and fatty acid oxidation, and decreased synthesis, suggesting that a lack of Ang-4 in adipose tissue enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. [204].

It has been estimated that predominantly Ang-2 is extensively expressed in tumor endothelial cells and, in association with VEGF and other proangiogenic factors, triggers tumor angiogenesis [36]. This is accompanied by the proteolytic degradation of the basement membrane by matrix metalloproteinases (MMPs), which results in the loosening of endothelial cell–cell junctions [36]. Nowadays, it is well established that the serum levels of Ang-2 are significantly associated with the onset and progression of non-small-cell lung cancer (NSCLC) [197]. Ang-2 transcription augments the migration, invasion, and EMT of lung cancer cells [205]. While the role of Ang-4 (which acts as an agonist of the Tie-2 receptor) in tumor angiogenesis and invasion seems unclear, Ang-4 was recently shown to be associated with cancer progression by promoting glucose metabolism in colorectal cancer [206].

NRF2 belongs to the group of redox-sensitive transcription factors expressed in several tissues and, by promoting ROS detoxification, improves oxidative stress and maintains redox homeostasis [207]. Kelch-like ECH-associated protein 1 (KEAP1) is an inhibitor of NRF2 [208], while heme oxygenase-1 (HO-1) is a target of NRF2, which induces its expression [209].

Based on the mentioned data, the NRF2 signaling pathway is currently considered an important defense mechanism against ASCVD; however, the mechanisms underlying the preventive effects of NRF2 are barely known. The nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) pathway confers antioxidant effects and plays a crucial protective role in cellular responses to oxidative stress, which is a risk factor for ASCVD, due to the degradation of pro-oxidant heme and the generation of antioxidants biliverdin and bilirubin [209].

NRF2 has paradoxical roles in cancer biology, either acting as a tumor suppressor or exerting oncogenic effects [210]. There are also conflicting data as to whether NRF2 promotes or inhibits tumor initiation because no studies have demonstrated that NRF2-activating mutations alone are sufficient to initiate cancer [210]. It is known that cancer cells, to limit the damaging effects of ROS, utilize the transcription factor NRF2 to upregulate antioxidant proteins [91]. This may be mediated through the activation of the pentose phosphate pathway (PPP), a major glucose catabolic pathway, which redirects glucose and glutamine into anabolic processes, especially under the sustained activation of oncogenic signaling [211]. During the early phases of tumorigenesis, ROS appear to be mutagenic, and therefore, they support cell transformation into cancer cells [84]. Evidence indicates that ROS increase upon transformation, but their levels are kept in check by antioxidant systems, as orchestrated by NRF2 [212]. It is possible that limiting ROS is necessary for the initiation of cell transformation, whereas sustaining ROS levels promotes metastasis [91]. Likely, during tumor progression, a different type of ROS is being affected, and high levels of toxic ROS (that is, O₂⁻, ⁻OH, LOOH) may be a barrier to tumor initiation; thus, initiation requires the elevated expression of both NRF2 activation and TP53-induced glycolysis and apoptosis regulator (TIGAR) to support toxic ROS scavenging [91]. Robust evidence for the importance of ROS in cancer comes from human cancer genetic analysis and studies showing that loss-of-function mutations in cytoplasmic KEAP1 result in the activation of NRF2 in the context of other cancer-promoting mutations [213]. Hence, the NRF2 regulation of the antioxidant response by eliminating ROS and maintaining a normal redox state can have a detrimental impact on cancer treatment [214]. NRF2/KEAP1 may also protect against aberrant inflammation by regulating the uncontrolled activation of the NF-κB pathway, which can result in inflammatory cell damage and lead to malignant cell transformation [215]. NRF2 upregulates HO-1, which, besides removing toxic heme, produces biliverdin, iron ions, and carbon monoxide and thus exerts beneficial effects by protecting against oxidative injury, the regulation of apoptosis, and the modulation of inflammation, as well as the contribution to angiogenesis [216]. However, the role of HO-1 in tumorigenesis has not been systematically addressed, although emerging data show the multiple roles of HO-1 in tumorigenesis, from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy [217].

Hypoxia-induced factor 1-alpha (HIF-1a), a heterodimeric protein part of the basic helix-loop-helix family, is regarded as the core molecule of an oxygen-sensing mechanism in the body, which is hypoxia [218,219].

HIF-1a in atherosclerosis exerts both detrimental and beneficial actions, depending on the cell type expressing HIF-1a [220]. OxLDLs can trigger HIF-1a activation through TLRs in macrophages, with consequences for interleukin-1β (IL-1β) production and the metabolic rewiring of macrophages with the induction of glycolysis (rather than OXPHOS) [220]. Overall, HIF-1a plays a key role in the critical steps of atherosclerosis development, acting on endothelial cells, vascular smooth muscle cells, and foam cell formation, and through the upregulation of VEGF, ROS, and the NF-kB pathways in endothelial cells, HIF-1a is able to cause endothelial cell dysfunction, angiogenesis, and inflammation [221].

HIF-1a, activated by hypoxia, is highly expressed in the TME and represents the main trigger for the growth of new blood vessels in malignant tumors [222]. HIF-1a induces the upregulation of angiogenic factors, VEGF/VEGFR, and angiopoietin with the Tie2 receptor at the transcriptional level, thereby promoting the formation of new blood vessels in cancer, leading to tumor growth, progression, and metastasis [180]. HIF-1a is also directly linked to leptin, which shows strong proangiogenic properties [223,224]. HIF-1a levels are regulated by multiple signaling pathways that play an important role in human cancer, among them the PI3K-Akt-mTOR signaling pathway [101]. PI3K/Akt signaling upregulates HIF-1a transcription and translation by PI3K/Akt signal, regardless of oxygen levels [225,226]. Both PI3K/Akt activity and HIF-1a expression are influenced by ROS. Collectively, these results suggest that ROS-induced high HIF-1a expression is, to a certain extent, mediated via PI3K/Akt activation [227]. HIF-1a is a key regulator of cancer metabolism. Deregulation of HIF-1a coupled with the abnormal expression of metabolic enzymes (pyruvate dehydrogenase complex) during cancer development might play a role in inducing the deviation of tumor cells from the default OXPHOS program to enter into a permanent aerobic glycolytic metabolic pathway as an adaptation to low oxygen tension, as the main metabolic pathway for generating ATP, even in the presence of oxygen [228].

Lipoproteins and lipid factors, important in the pathophysiology of atherosclerosis, that have been shown to play a pro-tumorigenic role in several cancers include oxidized LDL (oxLDL), Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1), Proprotein Convertase Subtilisin/Kexin type-9 serine protease (PCSK9), and other specific components, like fatty acid synthase (FASN) [229,230]. These specific components of the lipogenic machinery and cholesterol homeostasis are subject to the regulation of master transcriptional regulators, which may comprise sterol regulatory element-binding proteins (SREBPs) and liver X receptors (LXRs) [231].

The oxidation of subendothelial LDL, oxLDL, is reported to be a major player in atherosclerosis development [232]. Also, oxLDL has been implicated in many aspects of cancer [229]. OxLDL upregulates HIF-1a expression and increases microRNA miR-210 expression, which leads to the downregulation of sprout-related EVH1 domain 2 (SPRED2), a protein that reduces cell migration, leading to a higher risk of vascular diseases [58]. Downregulation of SPRED2 has been detected in advanced human cancers and is associated with highly metastatic phenotypes [233,234]. OxLDL may disrupt the barrier integrity of the endothelium and represents one of the strongest triggering factors for the transition of endothelial cells into mesenchymal-like cells under pathological conditions, like in the context of atherosclerosis and cancer [235]. The induction of autophagy is an important additional mechanism by which oxLDL participates in cancer progression and promotes EMT when spreading outside the tumor mass [236]. This may be through oxLDL activation of the key metabolic enzyme proline oxidase (POX), which produces superoxide, which exerts its effect by regulating beclin-1 [237].

The majority of the atherogenic effects of oxLDL on endothelial function are regulated through the expression and activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) [58]. LOX-1 belongs to class E scavenger receptors (SRs) and has the ability to bind to dysfunctional lipids, like oxLDL, fundamental in atherosclerosis and other diseases, like obesity, hypertension, and cancer [238]. LOX-1 is upregulated by many inflammatory mediators and proatherogenic stimuli but has no known enzymatic or catalytic activity, and ligand binding has been shown to trigger intracellular signaling [18,239]. To date, evidence suggests that LOX-1 is involved in a plethora of processes relevant to the pathogenesis of certain malignancies and may play a causative role in tumor initiation and progression [58]. LOX-1 overexpression mediates VEGF induction and HIF-1a activation, promoting neoangiogenic and EMT processes in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors [240]. In endothelial cells, the binding of oxLDL to LOX-1 increases ROS formation, the PI3K/Akt cascade, and NFkB activation [240,241].

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, is now identified as an important and major player in the pathophysiology of atherosclerosis and promotes the onset and progression of CVD [242]. PCSK9 is activated when intracellular cholesterol is reduced and binds to LDL-Rs, redirecting them to lysosomes for cleavage instead of recycling them back to the cell surface, promoting a subsequent increase in LDL-cholesterol (LDL-C) levels [243]. Beyond cholesterol metabolism, other physiological processes are also regulated by PCSK9, such as adipogenesis modulation, the immune response, and interaction with many other cellular receptors, including LOX-1 [244].

PCSK9 can mediate oxLDL-induced inflammation by enhancing the expression of LOX-1, which can increase the uptake of oxLDLs that induce inflammation via activation of NF-kB. PCSK9 can also increase the expression of TLR4, which activates NF-kB to upregulate the expression of inflammatory cytokines, like interleukin 6 (IL-6) [242]. Silencing PCSK9 reduced the expression of inflammatory genes by blocking the TLR4/NFkB pathway in macrophages [245]. PCSK9 increases oxLDL uptake and activates ROS [246]. Given these observations, PCSK9 is clearly involved in the inflammatory response of atherosclerosis.

The recent literature illustrates that PCSK9 is highly expressed and strongly associated with the incidence and progression of most cancers [247]. Τhe use of PCSK9 small interfering RNA (PCSK9i) also enhanced the efficacy of immune therapy targeted at the checkpoint protein PD-1 [248]. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer [249]. Hence, a novel application of PCSK9 inhibitors in cancer and metastasis could be considered. However, due to poor data on the effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition on these pathological conditions is still unknown [250].

Sterol regulatory element-binding proteins (SREBPs) are transcription factors for cholesterol production and absorption, and they regulate one of the critical transcription pathways involved in cholesterol homeostasis [251]. Generally, SREBP-1 activates the synthesis of fatty acids and triglycerides, while SREBP-2 increases the synthesis of cholesterol [252]. Activation of SREBP transcription leads to the increased expression of microRNA-33, specifically miR-33a and miR-33b, which are located within intron 16 of SREBP-2 and intron 17 of SREBP-1, respectively [253]. The co-expression of the two miR-33 forms, along with their host genes, can function in a synergistic manner to further facilitate lipid homeostasis [254]. miRNAs are small non-coding RNAs that are key regulators of metabolism and play an important role in cancer by actually downregulating SREBPs in cancer cells [255,256].

The activation of SREBP-1 and -2 ultimately upregulates the expression of enzymes in lipogenesis pathways and the expression of LDLRs, promoting fatty acid and cholesterol synthesis, while LDLR upregulation increases cholesterol uptake [257]. SREBP-1 and -2 also regulate the expression of PCSK9 [258]. SREBP2 was identified as a potent activator of the NLRP3 inflammasome in ECs [259]. In support of the above finding, SREBPs may exacerbate the initiation and progression of atherosclerosis [260].

SREBPs are significantly upregulated in human cancers and mediate a mechanistic link between lipid metabolism reprogramming and malignancy [261]. SREBPs are activated in a lipid-independent manner in cancer by the PI3K/Akt/mTOR/SREBP1 signaling pathway, which is often abnormally activated in tumor cells. Activation of the PI3K/Akt/mTOR signaling pathway induces the transcription of SREBPs, which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells [58]. Moreover, PI3K/Akt/mTOR/SREBP1 signaling protects cancer cells by inhibiting ferroptosis, an iron-dependent form of cell death caused by the accumulation of phospholipid peroxides [262]. SREBP1 inhibits ferroptosis in cancer cells by upregulating its transcriptional target SCD1 and producing monounsaturated fatty acids [263]. In situations in which lipids and/or oxygen is limited, SREBP2 and its downstream targets, including mevalonate-pathway enzymes, are significantly upregulated [264]. The upstream mevalonate pathway is oncogenic in a variety of cancers, mainly in brain tumors like glioblastoma, and requires the oncogene MYC for its upregulation [265,266]. This upregulation of the mevalonate pathway further upregulates the microRNA miR-33b; however, it is still not entirely clear whether the lipid accumulation induced by microRNAs through SREBPs has a direct link to the cancer cell phenotype [263]. Whereas oncogene activity promotes cholesterol upregulation, tumor suppressors have the opposite effect. For example, the well-known tumor suppressor p53 upregulates ABCA1, thereby restricting SREBP2 maturation and repressing the mevalonate pathway [267].

Specific components of the lipogenic machinery have been shown to play a pro-tumorigenic role in several cancers. These master transcriptional regulators governing cholesterol homeostasis and lipid metabolism are indispensable for tumor progression and include those discussed below.

Fatty acid synthase (FASN) or fatty acid translocase or cluster of differentiation 36 (CD36) is a transmembrane glycoprotein that acts as a downstream molecular complex that facilitates intercellular cholesterol and free fatty acid (FFA) transport [268]. FASN is one of the key components that link lipid synthesis, oxidative stress, and ROS formation, as shown in p53-deficient colorectal cancer cells, where ROS-mediated FASN stabilization promotes lipid synthesis and tumor growth [269]. FASN also acts as a signal-transducing receptor for oxLDL [270]. Once FFAs are taken up into the cell, they can be stored in lipid droplets and used for fatty acid β-oxidation and energy production [270]. This may be regulated through the liver kinase B1/LKB1-AMPK pathway [268]. In addition to the exogenous uptake and release of FFAs, FASN could induce insulin resistance and β-cell dysfunction [271]. FASN, as a key downstream target of SREBP, brings fatty acids into cancer cells and is upregulated in breast, prostate, ovarian, stomach, and colorectal cancers and also in many other types of cancers [272].

High CD36/FASN expression is associated with a poor prognosis in cancers, such as breast, ovarian, gastric, and prostate cancer [85]. Increased FASN expression correlates with established oncogenic events, like human epidermal growth factor receptor 1,2 (HER1/2) amplification in breast cancer, which in turn induces the expression of FASN via activation of PI3K/Akt pathways, resulting in positive feedback to maintain elevated levels of FASN in cancer cells [273]. FASN upregulation and overexpression in cancer cells lead to increased lipid synthesis, in addition to mTOR activation, resulting in increased protein synthesis. FASN also favors the activity of the PPP (pentose phosphate pathway) enzyme PGDH by increasing the pool of NADP+, a co-substrate of the latter. PPP upregulation concomitantly increases DNA/RNA synthesis [274]. The uptake of FFAs (such as oleate and palmitate) via FASN activates oncogenic signaling pathways in liver cancer cells, thereby promoting EMT [275]. FASN/CD36 can also activate the Wnt signaling pathway to promote metastasis through EMT [268].

Liver X receptors (LXRs) are transcription factors that belong to the nuclear hormone receptor family. They play a role in lipid metabolism regulation. They act as cholesterol and glucose sensors, ultimately promoting the loss of cellular cholesterol and regulating insulin sensitivity and whole-body homeostasis [276]. LXRs counterbalance the activity of SREBPs, which enhances lipid uptake and biogenesis to maintain cholesterol homeostasis, reversing cholesterol transport and limiting lipid uptake when cellular lipid stores are high [276]. LXRs are nuclear receptors that also modulate intracellular cholesterol levels by upregulating the transcription of efflux proteins such as ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1), which are cell membrane proteins that allow cholesterol efflux from cells. ABCA1 is required for high-density lipoprotein (HDL) biogenesis, efflux of cholesterol from macrophages, and reverse transport of cholesterol to the liver [276]. Thus, LXR activity within lesions is atheroprotective [277,278]. Recent studies have demonstrated that TIGAR, which protects against glycolysis and oxidative stress, is associated with ASCVD by upregulating ABCA1 and ABCG1, also interfering with LXR expression via ROS [279]. The activation of LXRs also results in an increase in HIF-1a transcriptional activity [220].

In cancer, LXRs contribute to the development of glioblastoma, a highly lethal brain cancer, which significantly depends on cholesterol and is overly sensitive to LXR-agonist-induced cell death [280]. Also, upregulation of ABCA1 and ABCG1 by LXR agonists has induced apoptosis in prostate and breast cancer cell lines [281]. In tumor immunotherapy, LXR activation therapy produces a strong anti-tumor response in mice and enhances the activation of T cells in various immunotherapy studies, suggesting the LXR/ApoE axis as a target for improving the efficacy of tumor immunotherapy [282]. LXRs contribute to the development of colorectal cancer, along with the enzyme Stearoyl-CoA Desaturase 1 (SCD1), which is directly regulated by LXRs [283]. TIGAR inhibition repressed SCD1 expression in a redox- and AMPK-dependent manner, and TIGAR also induces ferroptosis resistance in colorectal cancer cells via the ROS/AMPK/SCD1 signaling pathway [284].

Desaturation is indispensable in cancer to avoid lipotoxicity under conditions of nutrient stress [272]. Desaturases are controlled by SREBP [272] and by LXRs [283]. In particular, the Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. SCD1 catalyzes the generation of monounsaturated fatty acids (MUFAs), which are major components of triglycerides stored in lipid droplets, to form new saturated fatty acid (SFA) substrates—making it a key enzyme involved in finely tuning the MUFA-to-SFA ratio [285].

SCD1 plays an important role in cancer, promoting cell proliferation and metastasis [286]. Its inhibition reduces the MUFA/SFA ratio and contributes to the induction of ferroptosis in tumor cells [287]. Intriguingly, despite LXR agonists eliciting great interest as a promising therapeutic target for cancer, LXR’s ability to induce SCD1 and new fatty acid synthesis represents a major obstacle in the development of new effective treatments [283].

The acetyl-CoA synthetase (ACSS) enzyme is the sole known mammalian enzyme that can catalyze the conversion of free acetate into acetyl coenzyme A (acetyl-CoA) for lipid synthesis. When cellular cholesterol levels fall below the threshold, proteases begin to act on SREBPs and promote the expression of genes related to cholesterol and fatty acid synthesis, like ACSS2 [288]. SREBP cooperates with the transcription factor LXR, accentuating the importance of ACSS2 in lipid synthesis [288].

More recently, ACSS2 was identified to facilitate the adaptation of cancer cells in the TME by promoting the acetylation of histones and transcription factors and therefore influencing metabolic reprogramming and cell cycle progression in tumors [34,289]. Of interest, to upregulate histone acetylation, ACSS2 forms a complex with TFEB [290]. In addition, studies on tumors have shown that, in cancer cells, ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4) and enhances IRF4 stability and IRF4-mediated gene transcription through the activation of acetylation [291]. Moreover, ACSS2 expression inversely correlates with overall survival in patients with triple-negative breast cancer, liver cancer, glioma, or lung cancer [34].

4. The Role of Adiposity in Cancer

4.1. White Adipose Tissue (WAT)

4.2. Brown Adipose Tissue (BAT)

4.3. Dysfunctional Adiposity and Cancer: The Role of LD Accumulation