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. 2024 Dec 18;8(1):36–46. doi: 10.1021/acsptsci.4c00476

Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases

Heba Ewida †,‡, Harrison Benson †, Syed Tareq †, Mahmoud Salama Ahmed †,*
PMCID: PMC11729435  PMID: 39816789

Abstract

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Acetyl coenzyme A (acetyl-CoA), a pivotal regulatory metabolite, is a product of numerous catabolic reactions and a substrate for various anabolic responses. Its role extends to crucial physiological processes, such as glucose homeostasis and free fatty acid utilization. Moreover, acetyl-CoA plays a significant part in reshaping the metabolic microenvironment and influencing the progression of several diseases and conditions, including cancer, insulin resistance, diabetes, heart failure, fear, and neuropathic pain. This Review delves into the role of acetyl-CoA in both physiological and pathological conditions, shedding light on the key players in its formation within the cytosol. We specifically focus on the physiological impact of malonyl-CoA decarboxylase (MCD), acetyl-CoA synthetase2 (ACSS2), and ATP-citrate lyase (ACLY) on metabolism, glucose homeostasis, free fatty acid utilization, and post-translational modification cellular processes. Additionally, we present the pathological implications of MCD, ACSS2, and ACLY in various clinical manifestations. This Review also explores the potential and limitations of targeting MCD, ACSS2, and ACLY using small molecules in different clinical settings.

Keywords: Acetyl-CoA, Malonyl-CoA decarboxylase, Acetyl-CoA synthetase2, ATP-citrate lyase, Metabolism, Small molecules

Acetyl-CoA is a critical regulatory metabolite that serves as a product of many catabolic reactions and a substrate for other anabolic reactions. Depending on the cell’s energetic state, acetyl-CoA is produced from the metabolism of glucose, fatty acids, and amino acids.1 Acetyl-CoA is composed of an acetyl moiety (CH3CO) linked to coenzyme A (CoASH) through a high-energy thioester bond. This enables the acetylation process to occur through transferring the acetyl group to many acceptor molecules.2 This transfer contributes to acetyl-CoA playing a central role in the synthesis of fatty acids, amino acids, and sterols in addition to histone acetylation. Acetyl-CoA is formed in the cell’s mitochondria, cytosol, and nucleus. In the mitochondrial matrix, acetyl-CoA is produced mainly from glycolysis and fatty acid β-oxidation according to substrate availability, circulating insulin and other hormones, and the physiologic demand. Malonyl-CoA decarboxylase (MCD), ATP-citrate lyase (ACLY), and acetyl-CoA synthetase 2 (ACSS2) are key enzymes involved in the synthesis of acetyl-CoA. MCD converts malonyl-CoA to acetyl-CoA, which is crucial for regulating the fatty acid metabolism. ACLY plays a pivotal role by converting citrate, exported from the mitochondria, into cytosolic acetyl-CoA and oxaloacetate, thus providing acetyl-CoA for fatty acid synthesis and other biosynthetic processes. ACSS2, on the other hand, converts acetate into acetyl-CoA in both the cytosol and nucleus using ATP (adenosine triphosphate). Together, these enzymes ensure a steady supply of acetyl-CoA, which is vital for various metabolic pathways and cellular functions.

Pyruvate is the final product of glycolysis, which is promoted by insulin signaling, and is introduced into the mitochondria through mitochondrial pyruvate carrier (MPC).3 The mitochondrial pyruvate undergoes oxidative decarboxylation by pyruvate dehydrogenase complex (PDC) to form acetyl-CoA.4 This PDC is composed of two regulatory compartments: pyruvate dehydrogenase kinase (PDK), which inhibits PDC, and pyruvate dehydrogenase phosphatase, which activates PDC.5 On the other hand, cytosolic acyl-CoA produced from free fatty acids is condensed with l-carnitine by carnitine palmitoyl transferase 1 (CPT1) to form acylcarnitine. The acylcarnitine is transported to the mitochondria through carnitine/acylcarnitine translocase, member 20 (SLC25A20), which is reconverted to l-carnitine and acyl-CoA by carnitine palmitoyl transferase 2 (CPT2). The produced acyl-CoA goes through β-oxidation to generate acetyl-CoA.6 Mitochondrial acetyl-CoA can also be made from mitochondrial acetate, formed from freely diffused acetaldehydes into the mitochondria.7 These aldehydes are converted to acetate by the aldehyde dehydrogenase 2 family, which then produces acetyl-CoA by acetyl-CoA-synthetase 1 (ACSS1)8 (Figure 1). Regarding cytosolic acetyl-CoA, mitochondrial citrate produced from tricarboxylic acid (TCA) is exported back to the cytosol through dicarboxylate antiporter solute carrier family 25 (SLC25A1) and converted by ACLY into acetyl-CoA and oxaloacetate.9 Cytosolic acetate synthesized from ethanol-derived acetaldehydes or derived from the extracellular milieu is used to synthesize acetyl-CoA using ACSS2 in an ATP-dependent manner.10 Additionally, cytosolic malonyl-CoA, which is produced by cytosolic acetyl-CoA carboxylase (ACC), and mitochondrial propionyl-CoA carboxylase are used for the production of acetyl-CoA using MCD.11 Acetyl-CoA is synthesized in the nucleus from acetate by ACSS2, from pyruvate by PDC, and from citrate by ACLY enzymes12 (Figure 1).

Figure 1.

Figure 1

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Cellular acetyl coenzyme A production. Abbreviations: ACC, acetyl-CoA carboxylase; ACLY, ATP-citrate lyase; ACSS1, acetyl-CoA synthetase 1; ACSS2, acetyl-CoA synthetase 2; CPT1, carnitine palmitoyl transferase 1; PDC, pyruvate dehydrogenase complex; MPC, mitochondrial pyruvate carrier; MCD, malonyl-CoA decarboxylase.

1. Physiological Role of Acetyl-CoA in Cellular Process Regulation

Under normal conditions, there is a balance in glucose, fatty acids, and amino acids and alcohol consumption as fuels. The mitochondrial acetyl-CoA, produced mainly by pyruvate dehydrogenase and β-oxidation of fatty acids, is incorporated into the citric acid cycle to produce NADH and FADH2, which then enter the electron transport chain through complex 1 and complex 2, respectively. The flow of electrons through the electron transport chain coupling with oxidative phosphorylation leads to the production of ATP13 (Figure 2). The excess acetyl-CoA is condensed with oxaloacetate to produce citrate, which is shuttled outside the mitochondria and cleaved in the cytoplasm by ATP-citrate lyase (ACLY) to produce acetyl-CoA and oxaloacetate. The cytoplasmic acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC), producing palmitate through fatty acid synthase.14 This conversion is considered the first step in regulating fatty acid synthesis by providing the essential building blocks for elongating the fatty acid carbon chain.15 Furthermore, in cases of starvation and/or overnutrition, acetyl-CoA is used to produce mitochondrial and cytosolic ketone bodies.16 Acetyl-CoA plays a regulatory role in protein acetylation by attaching the acetyl group onto the lysine of the side chain of the targeted protein.17 Protein acetylation occurs either by non-enzymatic acetylation or enzymatically using histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). The increased levels of acetyl-CoA determine the catalytic activity and substrate specificity of HAT enzymes and lead to optimal HAT activity.18 KATs can acetylate lysine residues on proteins other than histones. While they were initially identified for their role in histone acetylation, KATs also modify a variety of non-histone proteins. These include transcription factors, metabolic enzymes, and structural proteins.19,20 Under hyperglycemic conditions or overnutrition, or when cells switch to using fatty acids as the primary fuel, acetyl-CoA levels excessively increase and elevate protein acetylation21 (Figure 2).

Figure 2.

Figure 2

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Physiological role of acetyl-CoA in cellular process regulation. Abbreviations: ACC, acetyl-CoA carboxylase; ACLY, ATP-citrate lyase; ETC, electron transport chain; FAS, fatty acid synthase; HAT, histone acetyltransferase.

2. Pathological Role of Acetyl-CoA in the Progression of Different Diseases

Acetyl-CoA is essential in the progression of multiple diseases, such as cancer, cardiometabolic diseases, and neurological disorders. The primary mechanism is metabolic reprogramming to overcome the lack of nutrients and oxygen.22

2.1. Acetyl-CoA Regulation in Cancer

Acetyl-CoA is a vital metabolic intermediate involved in both anabolic and catabolic pathways.2 Cancer cells primarily rely on lipid metabolism for their growth and use histone acetylation to enhance the expression of genes that promote cancer.23 As the main product of fatty acid oxidation and a precursor for lipid biosynthesis, Acetyl-CoA plays a central role in the acetylation of various molecular substrates, which contributes to cancer growth, proliferation, and metastasis.18,24

In 1924, Otto Warburg described the metabolic environment of cancer cells and tumors, noting their high glucose consumption. Despite the presence of oxygen and functioning mitochondria, most of this glucose is fermented into lactate.25 This creates a substrate gap and increases the reliance on fatty acid uptake for β-oxidation, resulting in significant metabolic reprogramming to combat cancer progression.26,27 Under hypoxic conditions, cells increase their reliance on glycolysis, which leads to the conversion of pyruvate to lactate. This process is facilitated by the inhibition of pyruvate dehydrogenase (PDH) through the action of pyruvate dehydrogenase kinase 1 (PDK1).

PDK1 is activated by hypoxia-inducible factor 1 (HIF-1) and phosphoglycerate kinase 1 (PGK1). The inhibition of PDH creates a gap in the substrates needed for the synthesis of cytosolic acetyl-CoA.28,29 To fill this gap, there is an increased demand for acetate, which leads to the activation of ACSS2. ACSS2 helps in the synthesis of acetyl-CoA from acetate.30

ACLY contributes to cancer progression by consuming cytosolic citrate, which is derived from nutrients like glucose and glutamine.31 This process promotes the synthesis of fatty acids, providing cancer cells with the necessary building blocks for rapid proliferation. Moreover, ACLY regulates several signaling pathways, including the mevalonate, PI3K-AKT, and AMPK-ROS pathways, which are crucial for cancer cell survival and growth.32,33 Elevated levels of ACLY have been observed in various types of cancer, such as lung, prostate, bladder, breast, liver, stomach, and colon tumors.34−36

Inhibition of ACLY activity by RNAi or pharmacologic inhibitors has been shown to induce growth arrest in tumor cells both in vitro and in vivo.37 Several studies reported cell-cycle arrest and apoptosis induction due to the antiproliferative effects of ACLY suppression.9,33 Therefore, ACLY has been considered as an emerging target for cancer treatment.

Acetate was identified as the precursor for acetyl-CoA as a fuel for the microenvironment toward the progression of different types of cancer. The increased expression of ACSS2 in cancer cells has been linked to metabolic reprogramming in cancer cells.38−40 ACSS2 has been shown to support the growth and survival of cancer cells by providing a source of acetyl-CoA for several metabolic pathways, including lipid synthesis, protein, and histone acetylation.10,41 Depletion of ACSS2 showed inhibition of cellular proliferation and tumorgenicity, such as triple-negative breast cancer,42 lung cancer,43 fibrosarcoma,44 glioblastoma,45,46 colorectal cancer,47 prostate cancer,48 and melanoma.49 Moreover, recent studies have identified a link between ACSS2 activity and the immune response, suggesting that ACSS2 may be involved in tumor immune evasion. Therefore, ACSS2 may represent a potential new target for cancer immunotherapy.50

The role of MCD in cancer progression has been a center of controversy. MCD–/– MCF7 cell lines recapitulated cytotoxicity by affecting malonyl-CoA metabolism, fatty acid synthesis, and fatty acid β-oxidation.51 That study showed the promising role of inhibiting MCD in the treatment of breast cancer. It also showed the promising role of inhibiting MCD in treatment of breast cancer. However, recent studies showed contradictory results, showing that restoration of MCD expression in renal cell carcinoma cells reduced malonyl-CoA levels, blocked de novo fatty acid synthesis, and promoted the movement of fatty acids into mitochondria for oxidation. This study demonstrated that MCD-mediated fatty acid catabolism disrupts lipid homeostasis, thereby inhibiting the progression of clear cell renal carcinoma.52 Another study showed that the overexpression of MCD in osteosarcoma inhibited cell proliferation, migration, and invasion.53 These studies indicate that the regulation of MCD through activation or inhibition varies, depending on the specific cancer cell types and their reliance on fatty acid oxidation and synthesis.

2.2. Acetyl-CoA Regulation in Cardiometabolic Diseases

Obesity usually occurs due to higher calorie intake than is burned by exercise or normal daily activities, leading to increased body mass index and abnormal or massive fat accumulation.54 Obesity is associated with leptin resistance, accumulating fat in non-adipose tissues like the pancreas, liver, and skeletal muscle.55 This leads to an imbalance between fatty acid oxidation and glucose utilization. Subsequently, this forms a series of cellular and pathological events such as lipotoxicity, diminished glucose oxidation, and type 2 diabetes development.56

Obesity and type 2 diabetes are independent risk factors for cardiovascular disease and heart failure. Hyperglycemia and insulin resistance associated with type 2 diabetes can lead to an inability to respond to regular changes in fuel availability. The inability of the heart to appropriately utilize glucose, heavy reliance on fatty acids for energy production, and oxidative stress lead to cardiometabolic disorders.57−59

Numerous studies have suggested a link between ACLY and cardiometabolic disorders such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis.60 This is because ACLY activity is regulated by insulin and other dysregulated metabolic hormones in these diseases. In obesity, increased ACLY activity in adipose tissue can lead to increased fatty acid biosynthesis, subsequent lipid accumulation, and insulin resistance development. Inhibition of ACLY has been shown to improve insulin sensitivity and reduce adiposity in animal models of obesity.61−63 Similarly, in type 2 diabetes, ACLY activity is increased in the liver, leading to increased gluconeogenesis and hyperglycemia. ACLY inhibition has been shown to improve glycemic control in animal models of diabetes.64 Additionally, clinical studies on either type 2 diabetes or cardiovascular disease individuals with genetic variants that mimic ACLY inhibition were associated with decreased risk for developing cardiometabolic complications and decreased low-density lipoprotein (LDL) cholesterol levels.65 In atherosclerosis, ACLY inhibition reduces lipid accumulation in artery walls, reducing inflammation, improving endothelial function, and reducing atherosclerotic lesion formation.66 Therefore, ACLY has emerged as a potential target for treating cardiometabolic disorders.

Recent studies have shown a link between ACSS2 and cardiometabolic disorders. ACSS2 expression was elevated in the adipose tissue of obese individuals, which promotes fat storage and utilization, and this was correlated with insulin resistance and metabolic dysfunction. Additionally, ACSS2 inhibition in obese mice improved insulin sensitivity and glucose metabolism.67,68

Several cellular and preclinical studies showed that inhibition of MCD by MCD knockout (MCD–/–) in the cell lines or in mice could inhibit fatty acid oxidation through the malonyl-CoA inhibitory effect for CPT1 to shift energy metabolism in cardiometabolic diseases.69−72 Several studies showed that inhibition of MCD is associated with improved insulin sensitivity and decreased inflammatory response in obese animal models.73,74 The absence of MCD led to the inhibition of fatty acid oxidation and stimulation of cardiac glucose oxidation, thus protecting the heart from ischemic injury and improving cardiac function post-myocardial infarction.71,75,76 Other studies showed that increased expression of MCD in the brain was associated with increased food intake and body weight due to diminished levels of malonyl-CoA.77

2.3. Acetyl-CoA Regulation in Fear, Neuropathic Pain, and Neurodegenerative Diseases

Histone acetylation is the primary regulator for long-term memory, including fear memory.78 Histone acetylation is balanced in the brain by the activity of histone acyltransferase (HAT) and histone deacetylase (HDAC).79 Acetyl-CoA is a substrate for histone acetylation. In the nucleus, ACLY, PDC, and ACSS2 play essential roles in the production of acetyl-CoA, which is used for histone acetylation.80 Different studies have shown that reducing ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of memory-related neuronal genes.81−83 Alexander et al. showed that ACSS2 knockout in mice or pharmacological inhibition of ACSS2 in rodents led to their reduced acquisition of long-term fear memory.84

This was associated with a reduction in histone acetylation due to decreased levels of acetyl-CoA.80 Additionally, the role of acetyl-CoA in neuropathic pain was related through its involvement in regulating the pathways associated with increased levels of reactive oxygen species and inflammatory markers. This leads to changes in the DNA structure and associated proteins that can alter gene expression.

Acetyl-CoA is involved in the synthesis of neurotransmitters, such as acetylcholine. Lower levels of acetyl-CoA can disrupt cholinergic neurotransmission, which is essential for cognitive functions and is significantly impacted in Alzheimer’s disease.85 The disruption in protein acetylation due to reduced acetyl-CoA levels has been linked to neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, affecting neuronal plasticity, memory, and learning.86 Research by Currais et al. demonstrated that increasing acetyl-CoA levels can mitigate brain aging and may offer a therapeutic approach for treating dementia.87

3. Pharmacological Strategies for Acetyl-CoA Inhibition

Based on the involvement, as mentioned earlier, of acetyl-CoA in the progression of different clinical indications, there have been various attempts to induce metabolic reprogramming by targeting the leading vital players regulating acetyl-CoA levels, including MCD, ACSS2, and ACLY. In this Review, we present different inhibitors that showed promising activities preclinically to regulate acetyl-CoA levels in various clinical settings.

3.1. Structural Basis of Malonyl-CoA Decarboxylase (MCD) Inhibitors and Clinical Significance

The crystal structure of human MCD (hMCD) was elucidated to provide structural insights into catalytic mechanisms. However, the crystal structures of hMCD with malonyl-CoA or acetyl-CoA had not been successfully resolved. Froese et al. reported that the MCD catalytic domain shares structural homology with the GCN5-related N-acetyltransferase superfamily, with a conserved His-Ser/Thr catalytic dyad induced by acetyl-CoA88 (Figure 3A). Here, we focus on the MCD inhibitors that were tested preclinically and whose pharmacokinetic (PK) parameters were elucidated (Figure 4A).

Figure 3.

Figure 3

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Resolved crystal structures of (A) hMCD (PDB ID: 2YGW), highlighting the catalytic dyad of Ser329 and His423; (B) ACSS2 isolated from Salmonella enterica at 1.75 Å (PDB ID: 2P2F), cocrystallized with AMP (red) and COA (blue); and (C) hACLY at 1.35 Å (PDB ID: 6HXL), cocrystallized with citrate (red) and COA (blue). These structures were generated using Pymol.

Figure 4.

Figure 4

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Examples of MCD, ACSS2, and ACLY inhibitors supported with chemical structures and developmental stages, whether validated via in vitro preclinical studies, in vivo preclinical studies, early phases of clinical trials, or FDA-approved.

In 2004, the Lopaschuck research group identified CBM-300864 and CBM-301940 as inhibiting MCD and decreasing fatty acid oxidation via elevating malonyl-CoA levels and accelerating glucose oxidation without changing glycolysis rates. Eventually, these analogs protected ischemic hearts in preclinical models including both rats and pigs. This was associated with pharmacodynamic changes to induce a metabolic switch in the energy substrate utilization to glucose.89

In 2006, Lopaschuck and Cheng’s groups collaborated to offer a complete profile for the free acid form of CBM-300864 that managed to block malonyl-CoA degradation and increase the glucose oxidation rates ex vivo in isolated rat hearts.90 They profiled the PK behavior for CBM-300864, showing a good permeability profile of 32.9 × 10–6 cm/s against Caco-2 cell lines. However, they did not show the permeability efflux ratio (ER) profiles, the binding profiles to different substrates such as P-glycoprotein, microsomal metabolic stability, or in vivo PK profiling.

Regarding CBM-301940, intravenous and oral administration of 10 mg/kg in Sprague–Dawley rats showed that it has more than 70% oral bioavailability, with a half-life (T1/2) of 2.3 h, Tmax of 0.5 h, and Cmax of 2683 ng/mL, which is equivalent to 6.5 μM.90

Also, CBM-300864 was validated for its role in inducing metabolic reprogramming in fatty acid synthesis and oxidation in breast cancer treatment via in vitro screening against MCF7 cell lines.91

Another study showed that the MCD inhibitor CBM-301106 (structure was not shown in the literature) was tested in ex vivo settings and found to reduce the inflammatory response in isolated cardiomyocytes of neonatal rats associated with insulin resistance. That work also showed that the mechanism involved the inhibition of MCD to induce CPT1 inhibition through increasing levels of malonyl-CoA. This leads to long-chain acyl-CoA accumulation, PPAR activation, and reduced levels of TNFα as well as NF-κB DNA binding.73

3.2. Structural Basis of Acetyl-CoA Synthetase 2 (ACSS2) Inhibitors and Clinical Significance

ACSS2 is a conserved nucleocytosolic enzyme that catalyzes the conversion of the acetate to acetyl-CoA. The whole kinetics for ACSS enzymes is based on the biuni–unibi ping-pong mechanism,92 where ACSS enzymes catalyze a two-step reaction in which acetate is first reacted with ATP to generate the adenylated ester (Ac-AMP). This Ac-AMP intermediate reacts with the thiol of coenzyme A to yield acetyl-CoA and AMP93 (Figure 3B).

Herein, we focus on the ACSS2 inhibitors that were tested preclinically and examples of inhibitors that were enrolled in earlier phases of clinical trials with elucidation of PK parameters (Figure 4B).

In 2016, AR-12, a celecoxib-based non-nucleoside derivative, showed a poor inhibitory profile for targeting hACSS2 while competing with ATP in a time-dependent manner. This was described as a part of AR-12’s mechanism for its fungicidal activity against S. cerevisiae and C. albicans, where AR-12-treated fungal cells showed similar phenotypes to the genetic knockdown of ACSS2, including autophagy, loss of cellular integrity, and decreased histone acetylation.94

In 2021, the Shug group offered VY-3-135 and VY-3-249, small molecules that showed selective inhibitory profiles on ACSS2 while not inhibiting either ACSS1 or ACSS3. They inhibit acetate-dependent fatty acid synthesis and inhibit the growth of triple-negative breast cancer cell lines in in vivo preclinical models. However, these small molecules were only effective in highly expressed ACSS2 tumors, with no effect on low expressed ACSS2 tumors.95In vitro PK studies using a human microsomal stability assay revealed T1/2 > 180 and 21 min for VY-3-135 and VY-3-249, respectively. In vivo PK studies for VY-3-135 showed Cmax = 4446 ng/mL at Tmax = 15 min and T1/2 = 0.73 h after a 10 mg/kg intraperitoneal dose in mice with high bioavailability. The short half-life of VY-3-135 can offer a potential opportunity for further structural optimization to improve the PK profile and identify the proper dosing frequency. Later, in 2022, the preclinical significance of VY-3-249 was shown to reduce histone acetylation, disrupt the acquisition of long-term fear memory formation, and reduce anxiety in a post-traumatic stress disorder (PTSD) mice model. This was associated with improved blood–brain barrier (BBB) penetration and brain bioavailability profiling in vivo.84

In 2023, VY-3-249 administration in diabetic nephropathy mice significantly improved kidney functions, including diabetic glomerular injury, and mitigated glomerular hypertrophy. These effects were observed with no difference in both body weight and glucose levels compared with vehicle-treated diabetic mice. This study validated that the kidney protective function of the ACSS2 inhibitor was due to autophagy restoration and inhibition of the mTORC1 pathway.96

Recently, AD-5584 and AD-8007 showed high metabolic stability and BBB permeability for the treatment of breast cancer brain metastasis in vitro. They led to a significant reduction in lipid storage associated with a decrease in colony formation and induction of cell death in an ex vivo orthotopic brain-slice tumor model.97 The clinical relevance of ACSS2 inhibitors is established in advanced solid tumors like colorectal, breast, and lung cancers. MTB-9655 showed a high inhibitory profile against ACSS2 activity, with IC50 = 0.15 nM, with anti-carcinogenic effects against human colorectal, breast, and lung cancers with high ACSS2 expression levels in vivo.98 This qualified MTB-9655 as the first oral ACSS2 inhibitor for a phase 1 clinical trial for patients suffering from advanced solid tumors. It was administrated for a cycle of 21 days as a daily dose of up to 255 mg in 10 patients. PK studies showed T1/2 = 6–12 h. That was combined with mild side effects like nausea and increased bilirubin levels.98 There is potential for MTB-9655 to be used in combination with standard chemotherapy agents, such as cisplatin and gemcitabine, enhancing its therapeutic efficacy. These preclinical studies introduce MTB-9655 as a novel approach to targeting cancer metabolism, especially in cancers with high ACSS2 expression.

3.3. Structural Basis of ATP-Citrate Lyase (ACLY) Inhibitors and Clinical Significance

ACLY catalyzes the ATP-dependent and CoA-dependent conversion of citrate to oxaloacetate and acetyl-CoA99,100 (Figure 3C).

Herein, we focus on the ACLY inhibitors that were tested preclinically and clinically with the elucidation of PK parameters (Figure 4C).

In 1977, the reactivity of (−)-hydroxycitrate was the first-in-class to be evaluated for its inhibitory profile targeting ACLY compared to the other isomers.101 Later, a series of (3R*,5S*)-ω-substituted 3-carboxy-3,5-dihydroxyalkanoic acids showed inhibitory profiles against ACLY catalytic activity as potential candidates targeting hyperlipidemia, showing reduction of triglycerides in cellular assays using HepG2 cells without in vivo preclinical validation.102

In 2007, BMS-303141 (2-hydroxy-N-arylbenzenesulfonamide-based analog) showed inhibitory profiles against ACLY catalytic activity. This was coupled with preclinical validation showing an in vivo phenotype to induce whole-body weight loss in high-fat diet-induced obese mice with lower plasma cholesterol, triglyceride, and glucose levels.

In 2022, novel macrocyclic-based derivatives were introduced as ACLY inhibitors, where NDI-091143 showed a promising inhibitory profile at IC50 = 44 nM, with T1/2 = 3.36 min, using human liver microsomal enzyme without further in vivo preclinical validation.103

In 2023, the effect of ACLY inhibitor SB-204990 on different metabolic pathways was tested in wild-type mice fed with either a healthy diet or a high-fat diet. The work showed that SB-204990 induced metabolic reprogramming in high-fat diet mice models through regulation of energy metabolism, mitochondrial function, mTOR signaling, and folate cycle. Surprisingly, it was found that SB-204990 induced insulin resistance and metabolic imbalance in the healthy diet mice cohort, indicating that positive effects are related to an unhealthy diet. That was accompanied by in vivo PK profiling after oral administration of 30 mg/kg provided an average of 4 μM plasma concentration after 2 h ingestion in the range of nontoxic concentrations used in in vitro studies.61

Bempedoic acid (ETC-1002) is the only FDA-approved drug targeting acetyl-CoA regulation to lower LDL in hypercholesterolemic patients with a potential reduction in body weight.104,105 The primary mechanism of action of bempedoic acid is generated based on its activation by long-chain acyl-CoA synthetase-1 to inhibit ACLY directly by competing with CoA at the CoA-binding site.106 In 2023, a randomized placebo-based clinical trial was conducted including around 13,970 patients, of which 6992 were allocated to the bempedoic acid group and 6978 to the placebo group, which showed significant reduction in LDL levels with bempedoic acid. That leads to a significant reduction in mortality resulting from cardiovascular stroke and myocardial infarction.107 Additionally, a recent study showed the prophylactic potential of bempedoic acid in non-diabetic patients to develop T2D and associated cardiometabolic diseases.108

4. General Conclusions and Limitations

In this Review, we highlighted the role of acetyl-CoA while regulating different physiological functions related to glucose homeostasis and fatty acid utilization. This was supplemented by the role of key enzymes responsible for acetyl-CoA formation within the cytosol and their expression levels in different diseases. We offered a progress report for the small molecules targeting ACSS2, MCD, and ACLY. Despite the crystal structures of ACSS2, MCD, and ACLY being resolved that can enable structure-based drug design efforts, bempedoic acid is the only FDA-approved drug targeting ACLY toward the treatment of hypercholesterolemia. There is still a huge gap to target ACSS2 and MCD therapeutically. The roles of CoASH and malonyl-CoA still need further mechanistic investigation physiologically and pathologically.

Acetyl-CoA is produced in the mitochondria, cytosol, and nucleus of cells. In the mitochondria, it is mainly formed from glycolysis and fatty acid β-oxidation with pyruvate being converted to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Cytosolic acetyl-CoA is generated from citrate exported from the mitochondria and converted by ATP-citrate lyase (ACLY), as well as from acetate via acetyl-CoA synthetase 2 (ACSS2). In the nucleus, acetyl-CoA is synthesized from acetate by ACSS2, from pyruvate by PDC, and from citrate by ACLY.

Under normal conditions, cells balance the use of glucose, fatty acids, amino acids, and alcohol as fuels. Mitochondrial acetyl-CoA, produced from pyruvate dehydrogenase and fatty acid β-oxidation, enters the citric acid cycle to generate NADH and FADH2, which drive ATP production through the electron transport chain. Excess acetyl-CoA is converted to citrate, transported to the cytoplasm, and used for fatty acid synthesis. Acetyl-CoA also regulates protein acetylation and can be used to produce ketone bodies during starvation or overnutrition.

Glossary

Abbreviations

ACC

Acetyl-CoA carboxylase

ACLY

ATP-citrate lyase

ACSS1

Acetyl-CoA synthetase 1

ACSS2

Acetyl-CoA synthetase 2

AMPK

AMP-activated protein kinase

BBB

Blood–brain barrier

CPT1

Carnitine palmitoyl transferase 1

CPT2

Carnitine palmitoyl transferase 2

FAS

Fatty acid synthase

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HIF-1

Hypoxia-inducible factor 1

KAT

Lysine acetyltransferase

MCD

Malonyl-CoA decarboxylase

MPC

Mitochondrial pyruvate carrier

PDC

Pyruvate dehydrogenase complex

PDH

Pyruvate dehydrogenase

PDK

Pyruvate dehydrogenase kinase

PGK1

Phosphoglycerate kinase 1

SLC25A1

Dicarboxylate antiporter solute carrier family 25

SLC25A20

Carnitine/acylcarnitine translocase, member 20

PK

Pharmacokinetics

ER

Efflux ratio

T1/2

Half-life time

Author Contributions

Research design and literature search: H.E., H.B., S.T., and M.S.A. Writing of the manuscript: H.E., H.B., S.T., and M.S.A. Revision of the manuscript: H.E. and M.S.A.

This work was funded by start-up funds offered by the School of Pharmacy and Office of Research and Innovation at the Texas Tech University Health Sciences Center.

The authors declare no competing financial interest.

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