Glycolysis and Citric Acid Cycle: A Comprehensive Discussion

Glycolysis and citric acid cycle are two basic metabolic pathways, which play a core role in cell energy production. Glycolysis occurs in the cytoplasm, which decomposes glucose into pyruvate to produce ATP and NADH. Pyruvate then enters mitochondria, is converted into acetyl-coa and enters the citric-CoA cycle. Citric acid cycle occurs in mitochondrial matrix, which further oxidizes acetyl-coa to produce ATP, NADH, FADH₂ and -CoA These two pathways together provide energy and metabolic intermediates for cell function and survival.

In this paper, glycolysis and citric acid cycle are comprehensively introduced, including their biochemical reactions, regulation mechanisms, interrelationships and physiological significance.

Simulated flux through the carbon metabolism explains decoupling of glycolysis and the TCA cycle and more flux through TCA cycle on poor carbon sources (Kim D et al., 2018).

Glycolysis: Mechanisms, Energy Yield, and Regulation

Glycolysis, a central energy pathway in both aerobic and anaerobic organisms, converts glucose into pyruvate while generating ATP. Occurring in the cytoplasm without oxygen dependence, this process is critical for cellular energy homeostasis. Below, we detail its enzymatic steps, energy output, and regulatory mechanisms.

Enzymatic Pathway

Glycolysis comprises 10 reactions divided into two phases:

1. Energy Investment Phase

Glucose Phosphorylation

• Enzyme: Hexokinase (or glucokinase in hepatocytes).
• Mechanism: Glucose + ATP → Glucose-6-phosphate (irreversible step, trapping glucose intracellularly).

Isomerization

• Enzyme: Phosphoglucoisomerase.
• Mechanism: Glucose-6-phosphate ↔ Fructose-6-phosphate.

Second Phosphorylation

• Enzyme: Phosphofructokinase-1 (PFK-1, rate-limiting).
• Mechanism: Fructose-6-phosphate + ATP → Fructose-1,6-bisphosphate.

Cleavage

• Enzyme: Aldolase.
• Mechanism: Fructose-1,6-bisphosphate → Dihydroxyacetone phosphate (DHAP) + Glyceraldehyde-3-phosphate (G3P).
• Note: DHAP isomerizes to G3P, funneling both into subsequent steps.

2. Energy Payoff Phase

Oxidation and ATP Synthesis

• Enzyme: Glyceraldehyde-3-phosphate dehydrogenase.
• Mechanism: G3P → 1,3-Bisphosphoglycerate + NADH.

Substrate-Level Phosphorylation

• Enzyme: Phosphoglycerate kinase.
• Mechanism: 1,3-Bisphosphoglycerate → 3-Phosphoglycerate + ATP.

Isomerization

• Enzyme: Phosphoglycerate mutase.
• Mechanism: 3-Phosphoglycerate → 2-Phosphoglycerate.

Dehydration

• Enzyme: Enolase.
• Mechanism: 2-Phosphoglycerate → Phosphoenolpyruvate (PEP).

Final ATP Generation

• Enzyme: Pyruvate kinase.
• Mechanism: PEP → Pyruvate + ATP.

Energy Output

• ATP Yield:
• Consumption: 2 ATP (investment phase).
• Production: 4 ATP (payoff phase).
• Net Gain: 2 ATP per glucose molecule.
• Reducing Equivalents: 2 NADH molecules, crucial for maintaining redox balance under hypoxia.

Regulatory Mechanisms

• Hexokinase
• Inhibition: Glucose-6-phosphate (product feedback).
• PFK-1
• Activators: AMP, Fructose-2,6-bisphosphate (enhances flux under low energy).
• Inhibitors: ATP, Citrate (suppresses glycolysis during energy surplus).
• Pyruvate Kinase
• Activation: Fructose-1,6-bisphosphate (feedforward stimulation).
• Inhibition: ATP, Alanine (signals energy sufficiency).

Regulation of HNSCC glycolysis (Kumar D., 2017).

The Citric Acid Cycle: Core Reactions and Regulation

The citric acid cycle (Krebs cycle or TCA cycle) is a central metabolic pathway in cellular respiration, occurring in the mitochondrial matrix of eukaryotes. It oxidizes acetyl-CoA—derived from carbohydrates, fats, and proteins—into carbon dioxide, generating energy carriers (NADH, FADH₂, GTP) that fuel ATP synthesis via oxidative phosphorylation.

Key Reactions and Enzymes

Citrate Synthesis

• Enzyme: Citrate Synthase
• Process: Acetyl-CoA combines with oxaloacetate to form citrate, releasing CoA-SH. This step initiates the cycle.

Isomerization to Isocitrate

• Enzyme: Aconitase
• Process: Citrate undergoes structural rearrangement to isocitrate, priming it for oxidative decarboxylation.

Oxidative Decarboxylation to α-Ketoglutarate

• Enzyme: Isocitrate Dehydrogenase
• Process: Isocitrate is oxidized, producing α-ketoglutarate, CO₂, and NADH.

Formation of Succinyl-CoA

• Enzyme: α-Ketoglutarate Dehydrogenase Complex
• Process: α-Ketoglutarate is converted to succinyl-CoA, generating NADH and CO₂.

Substrate-Level Phosphorylation

• Enzyme: Succinyl-CoA Synthetase
• Process: Succinyl-CoA is converted to succinate, yielding GTP (or ATP).

Succinate Oxidation to Fumarate

• Enzyme: Succinate Dehydrogenase
• Process: Succinate loses electrons to FAD, forming fumarate and FADH₂.

Hydration to Malate

• Enzyme: Fumarase
• Process: Fumarate reacts with water, producing malate.

Regeneration of Oxaloacetate

• Enzyme: Malate Dehydrogenase
• Process: Malate is oxidized to oxaloacetate, regenerating NADH and restarting the cycle.

Energy Output

• Per Cycle: 3 NADH, 1 FADH₂, 1 GTP (or ATP).
• Per Glucose Molecule (two cycles): 6 NADH, 2 FADH₂, 2 GTP.
• Total ATP Yield: These carriers contribute to ~20–24 ATP via oxidative phosphorylation.

Regulatory Mechanisms

Citrate Synthase

• Inhibitors: ATP, NADH, succinyl-CoA (suppress activity under high energy).

Isocitrate Dehydrogenase

• Activators: ADP, Ca²⁺ (signal low energy).
• Inhibitors: ATP, NADH (prevent excess NADH production).

α-Ketoglutarate Dehydrogenase

• Inhibitors: Succinyl-CoA, NADH (feedback control to limit flux).

Functional Significance

The cycle's regulation ensures metabolic flexibility, balancing ATP synthesis with substrate availability. By modulating enzyme activity, cells adapt to energy demands, optimizing resource allocation between anabolism and catabolism. This dynamic control underscores the TCA cycle's role as a metabolic hub, integrating nutrient oxidation with cellular energy homeostasis.

Integration of Glycolysis and the Citric Acid Cycle

Pyruvate Oxidation

The glycolytic pathway generates pyruvate in the cytoplasm, which is subsequently transported into mitochondria. Here, the pyruvate dehydrogenase complex (PDC) catalyzes its oxidative decarboxylation to acetyl-CoA, a critical substrate for the citric acid cycle. This reaction releases CO₂ and generates NADH, linking cytoplasmic glycolysis to mitochondrial energy production. Acetyl-CoA serves as the primary input for the citric acid cycle, enabling continuous ATP synthesis under aerobic conditions.

Aerobic vs. Anaerobic Metabolism

Aerobic Conditions

In oxygen-rich environments, acetyl-CoA enters the citric acid cycle, undergoing sequential enzymatic reactions that yield NADH, FADH₂, and GTP. These reducing equivalents drive oxidative phosphorylation, producing ~30–32 ATP per glucose molecule. Oxygen acts as the terminal electron acceptor, maximizing energy efficiency.

Anaerobic Conditions

During oxygen scarcity (e.g., intense muscle activity or hypoxic environments), pyruvate is diverted into fermentation pathways. In animal cells, lactate dehydrogenase reduces pyruvate to lactate, regenerating NAD⁺ to sustain glycolysis. In yeast, pyruvate decarboxylation yields ethanol and CO₂. While fermentation produces only 2 ATP per glucose, it ensures short-term ATP supply by recycling NAD⁺.

Metabolic Adaptability

Shared Intermediates and Cofactors

Glycolysis and the citric acid cycle are interconnected through metabolites (e.g., pyruvate, acetyl-CoA) and redox coenzymes (NAD⁺/NADH). This synergy allows cells to dynamically balance ATP production with redox homeostasis.

Regulation by Energy Demand and Oxygen Availability

• High Energy Demand: Cells prioritize glycolysis for rapid ATP generation, even at low efficiency. Fermentation dominates under hypoxia, bypassing the citric acid cycle to maintain NAD⁺ levels.
• Low Energy Demand or Oxygen Sufficiency: Oxidative metabolism predominates, leveraging the citric acid cycle and electron transport chain for high-yield ATP production.

Complementary Pathways

Under aerobic conditions, acetyl-CoA fuels the citric acid cycle, supporting oxidative phosphorylation. During hypoxia, glycolysis and fermentation act as fail-safes, preventing metabolic gridlock. This duality highlights cellular adaptability to fluctuating energy requirements and environmental stressors.

Physiological and Practical Significance

Core Physiological Roles

ATP Synthesis

• Primary Energy Contribution: Glycolysis and the citric acid cycle serve as the principal ATP sources for cellular functions.
• Electron Carrier Utilization: NADH and FADH₂ generated by these pathways fuel electron transport chain-driven oxidative phosphorylation, amplifying ATP yield.

Precursor Supply for Anabolism

• Biosynthetic Substrates: Intermediate metabolites (e.g., acetyl-CoA, α-ketoglutarate) act as precursors for amino acids, nucleotides, and fatty acids, supporting macromolecule synthesis.

Redox Homeostasis

• Cofactor Recycling: Both pathways regenerate NAD⁺ and FAD, sustaining cellular redox equilibrium and enabling continuous metabolic activity.

Disease Mechanisms and Therapeutics

• Pathological Links: Dysregulation of these pathways is implicated in cancer (Warburg effect), diabetes (mitochondrial dysfunction), and neurodegeneration (oxidative stress).
• Therapeutic Targets: Modulating glycolytic or TCA cycle enzymes (e.g., HK2, IDH1/2) offers potential for precision medicine.

Industrial Biotechnology

• Microbial Engineering: Metabolic rewiring of glycolysis and the TCA cycle in organisms like E. coli or yeast enhances biofuel (e.g., ethanol, butanol) and pharmaceutical production.

Exercise Science

• Energy Dynamics: During physical exertion, glycolysis rapidly generates ATP for short-term bursts, while the TCA cycle supports endurance via oxidative metabolism. Optimizing these pathways improves athletic performance and recovery.

Application

The study revealed significant alterations in metabolites associated with the TCA cycle and glycolysis in the plasma of melanoma patients, including changes in levels of pyruvate, fumarate, 2-oxoglutarate, and glucose. Researchers explored the role of the TCA cycle in melanoma, focusing on the expression changes of PDHA1 (pyruvate dehydrogenase subunit 1) and OGDH (2-oxoglutarate dehydrogenase). Analysis of gene expression data indicated a marked increase in the expression of these enzymes in melanoma, with elevated PDHA1 levels correlating with poorer patient prognosis. Suppressing PDHA1 or OGDH expression significantly inhibited melanoma cell proliferation and induced cell cycle arrest. Additionally, pharmacological inhibitors like CPI613 were shown to impede melanoma cell growth, and combining these inhibitors with anti-PD-1 immunotherapy enhanced therapeutic efficacy. In melanoma mouse models, dual inhibition of PDHA1 and OGDH not only improved the effectiveness of anti-PD-1 immunotherapy but also extended survival. Immune microenvironment analysis further demonstrated that this combined therapy altered the tumor microenvironment by reducing the ratio of myeloid suppressor cells to macrophages and increasing the infiltration of functional CD4+ and CD8+ T cells. Inhibition of PDHA1 and OGDH, whether through genetic or pharmacological means, resulted in upregulated PD-L1 expression in melanoma cells. Inhibition of the TCA cycle reduced oxidative phosphorylation (OXPHOS), ATP production, and maximal respiratory capacity, while upregulating glycolytic flux, which in turn influenced PD-L1 expression. Enhanced glycolysis appeared to be linked to the upregulation of PD-L1. Following TCA cycle inhibition, the AMPK-CREB-ATF3 signaling pathway was activated, leading to increased glycolysis and PD-L1 expression. The critical role of ATF3 in regulating glycolysis and PD-L1 expression was confirmed. ATF3 was found to modulate glycolysis through HKDC1, and knocking down ATF3 significantly suppressed both glycolysis and PD-L1 expression. Single-cell sequencing data revealed that ATF3 and glycolysis-related enzymes (such as HK, PFKM, and PFKP) were highly expressed in tumor tissues that responded well to anti-PD-1 therapy (Liu N ET AL., 2023).

With the global rise in the aging population, the significance of research on neurodegenerative diseases has become increasingly prominent. In experiments involving mouse brains, the administration of turmeric root extract was observed to decrease levels of neurodegenerative markers linked to Alzheimer's disease (AD). Similarly, treatment with CRE (curcumin-rich extract) also reduced these markers, especially after alleviating stress indicators associated with impaired ER function. Post-CRE treatment, a reduction in glycolysis-related genes and ECAR was noted, signaling a decline in glycolytic activity.In parallel, both animal and cellular models subjected to CRE treatment displayed an upregulation of genes tied to the mitochondrial TCA cycle and OXPHOS, indicating that CRE might regulate energy metabolism by improving mitochondrial efficiency. The investigation also explored curcumin's impact on energy metabolism by assessing proteins associated with glycolysis and OXPHOS. While proteins such as HK1 and LDHA, linked to glycolysis, were elevated in the CRE-treated group, other proteins like PDH and PKM2 showed reduced levels. Additionally, CRE treatment significantly enhanced the expression of genes involved in the TCA cycle and OXPHOS. These outcomes were further corroborated in DBT cell lines, where CRE treatment resulted in diminished glycolytic activity and increased expression of TCA cycle and OXPHOS-related genes. The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was utilized to validate these results, demonstrating decreased levels of glycolysis-related proteins (e.g., HK1 and PKM2) and altered expression of TCA cycle genes (e.g., Aco2, Ogdh, and Mdh2) in DBT cells. OXPHOS-related genes were upregulated in the 2-DG-treated group, although certain genes (e.g., slc25a4) exhibited reduced expression.Dichloroacetic acid (DCA), a TCA cycle activator, was also used in the study. DCA treatment led to increased expression of TCA cycle-related genes (e.g., Aco2, Ogdh, Mdh2, and Sdhb) and OXPHOS-related genes (e.g., ATP5b and slc25a4) in DBT cells. In an animal model treated with CRE, notable reductions in APP and tau proteins were observed, along with decreased levels of glycolysis-related proteins (e.g., PKM2 and PDH) and increased LDHA levels. TCA cycle genes (e.g., Aco2, Ogdh, and Sdhb) were also upregulated in the CRE-treated group. These results indicate that CRE treatment has multifaceted effects on glycolysis, TCA cycle, and OXPHOS-related genes and proteins, potentially influencing the pathological processes associated with Alzheimer's disease (Jo SL ET AL., 2022).

In mammalian cells, glucose metabolism varies across different stages of the cell cycle. During the G1 phase, cells predominantly utilize the TCA cycle for glucose metabolism, whereas in the S phase, glycolysis becomes the preferred metabolic pathway. The coordination between the cell cycle and metabolism is largely mediated by Skp2, a protein associated with cell cycle regulation. Specifically, Skp2 facilitates the timely degradation of IDH1/2, key enzymes in the TCA cycle, through a dependent mechanism.This degradation process causes fluctuations in the abundance of IDH1 protein throughout the cell cycle, thereby regulating the switch between the TCA cycle and glycolysis. In prostate cancer cells, elevated Skp2 levels lead to IDH1 protein instability, which enhances glycolysis. This shift toward glycolysis creates favorable conditions for tumor development. S-phase cells exhibit high glycolytic rates but low TCA cycle activity, whereas G1-phase cells primarily rely on the TCA cycle with relatively lower glycolysis. Using 13C-labeled glucose or glutamine for metabolic analysis, researchers observed high glycolytic flux and increased PPP activity in S-phase cells. These metabolic changes are linked to the synthesis of biomacromolecules, such as fatty acids, aromatic amino acids, and nucleic acids, as well as DNA replication during the S phase. Additionally, the protein levels of IDH1 and IDH2, critical enzymes in the TCA cycle, fluctuate during the cell cycle, with their abundance being particularly low in the S phase. Although mRNA levels of these enzymes remain stable, their protein stability appears to be regulated. The loss of IDH1 and IDH2 disrupts TCA cycle flux and increases glycolysis rates. The importance of IDH1 and IDH2 in cellular metabolism was confirmed through CRISPR/Cas9 knockout experiments. Depletion of IDH1 or IDH2 results in mitochondrial dysfunction, elevated oxidative stress, and altered cell metabolism, especially in galactose medium, underscoring their role in maintaining normal metabolic and energy balance.During the cell cycle, Skp2 depletion significantly alters IDH1 stability and affects metabolic transitions, particularly in the S phase, where intermediate levels of glycolysis and TCA cycle activity shift. Cyclin E/CDK2 and cyclin A/CDK2 complexes promote the degradation of IDH1 and IDH2 by phosphorylating a specific site (T157) on IDH1. Phosphorylation at T157 triggers ubiquitination and subsequent degradation of IDH1 through Skp2 binding. Mutating the T157 site (T157A) prevents IDH1 degradation, eliminating cell cycle-dependent metabolic transitions, impairing cell proliferation, and inhibiting tumor formation both in vitro and in vivo. This demonstrates that IDH1 degradation supports periodic metabolic changes during the cell cycle, facilitating rapid growth and tumorigenesis. By either depleting Skp2 or overexpressing it in cells with low Skp2 levels, researchers found that Skp2 influences the stability of IDH1 and IDH2, thereby modulating metabolic pathways. Skp2 degradation is closely tied to metabolic transitions, particularly in balancing glycolysis and the TCA cycle. Treatment with Skp2 inhibitors, such as SKPin C1, leads to the accumulation of IDH1 and IDH2, shifting metabolism from glycolysis to the TCA cycle, mirroring the effects of Skp2 depletion. Furthermore, the metabolic transformation induced by SKPin C1 treatment depends on the presence of IDH1/2 (Liu J et al., 2020).

In normal mammalian cells, ATP is primarily generated through OXPHOS, whereas cancer cells predominantly rely on glycolysis, even under oxygen-rich conditions. When glycolysis is inhibited, cancer cells enhance mitochondrial activity and shift their reliance to OXPHOS to sustain ATP production and ensure survival. This metabolic shift is accompanied by changes in the intracellular metabolic profile, characterized by a reduction in TCA cycle intermediates, such as citric acid, and an increase in the levels of most amino acids. Glutamine and glutamic acid play a critical role in this metabolic reprogramming, as they are primarily channeled into the TCA cycle to meet cellular energy demands when glycolysis is suppressed.Autophagy also plays a significant role in regulating mitochondrial function following glycolysis inhibition. Through autophagy, cells can fine-tune mitochondrial activity, ensuring that their energy requirements are met and promoting cell survival. In response to glycolysis inhibition, cancer cells compensate for energy deficits by upregulating mitochondrial function, enhancing the TCA cycle, and increasing amino acid metabolism. Autophagy further aids cancer cells in adapting to glycolysis inhibition by supplying amino acids and maintaining mitochondrial integrity. Research suggests that combining glycolysis inhibition with mitochondrial OXPHOS suppression could be an effective therapeutic strategy against cancer, particularly when used alongside other anticancer treatments.Altering the sugar source in the culture medium significantly reduces lactic acid release, indicating the inhibition of glycolysis. Under such conditions, the proliferation of PANC-1 cells decreases, although cell survival remains largely unaffected. While glycolysis inhibition suppresses cell proliferation, it does not induce cell death. Instead, PANC-1 cells adapt by altering their metabolic pathways, such as increasing amino acid levels and decreasing TCA cycle intermediates, demonstrating that upregulated amino acid metabolism and mitochondrial function support cell survival. Following glycolysis inhibition, mitochondrial function is enhanced, as evidenced by increased mitochondrial membrane potential and clearer mitochondrial morphology, both of which indicate heightened mitochondrial activity and sustained ATP production (Shiratori R et al., 2019).

Under aerobic conditions, cancer cells exhibit a high rate of glucose consumption, relying on glycolysis and lactic acid fermentation to generate ATP, a phenomenon known as the Warburg effect. This metabolic adaptation enables cancer cells to produce sufficient biomass materials through glycolysis to support rapid cell growth and helps them survive in hypoxic microenvironments. PGK1, the first ATP-producing enzyme in glycolysis, plays a pivotal role in this process. Its activity is regulated by O-GlcNAc modification, particularly at the threonine 255 (T255) site. This modification enhances PGK1 activity, further promoting lactic acid production. Beyond activating glycolysis, O-GlcNAc modification also facilitates PGK1's translocation to mitochondria, where it inhibits the PDH complex, thereby reducing oxidative phosphorylation, a critical process in the TCA cycle. Blocking the T255 O-GlcNAc modification of PGK1 has been shown to reduce colon cancer cell proliferation, suppress glycolysis, enhance TCA cycle activity, and inhibit tumor growth in xenotransplantation models. Additionally, elevated O-GlcNAc levels of PGK1 have been observed in colon cancer patients, highlighting its role as a key regulatory pathway that coordinates glycolysis and the TCA cycle to promote tumor progression.The depletion of PGK1 using shRNA significantly reduced the proliferation of colon cancer cells, such as LoVo, HCT-116, and HT-29, underscoring its essential role in cancer cell growth and tumor development. PGK1 depletion also markedly decreased glycolytic activity, as evidenced by reduced extracellular acidification rates, suggesting its critical function in glycolysis. PGK1 is regulated by O-GlcNAc glycosylation, with chemical enzyme labeling and mass spectrometry identifying T255 and other sites as targets for this modification. This process is dynamically influenced by metabolic stresses, including oxidative stress, hypoxia, and high glucose levels. The T255 site is the primary glycosylation site of PGK1. Overexpression of OGT (O-GlcNAc transferase) in PGK1 wild-type (WT) cells led to increased glucose uptake, elevated lactic acid production, and a decreased ADP/ATP ratio, indicating enhanced glycolysis and reduced oxidative phosphorylation (OCR). These findings suggest that glycosylation modification promotes cell proliferation by altering metabolic pathways. In contrast, PGK1 T255V mutant cells exhibited lower glycolytic activity and higher levels of TCA cycle metabolites, demonstrating that T255 glycosylation regulates the balance between glycolysis and the TCA cycle, thereby influencing cellular metabolism (Nie H et al., 2020).

Research has demonstrated that HSulf-1, a recognized potential tumor suppressor, can influence the metabolic activity of cancer cells by modulating the glycolytic pathway. Suppressing HSulf-1 expression results in the upregulation of glycolysis-related genes, such as Glut1, HKII, and LDHA, leading to increased glucose uptake and lactic acid production, indicative of enhanced aerobic glycolysis, or the Warburg effect. Conversely, overexpression of HSulf-1 reduces the expression of glycolytic enzymes and diminishes glycolysis-related phenotypes. These findings suggest that the loss of HSulf-1 may promote aerobic glycolysis in ovarian cancer cells. In OVCA cells with downregulated HSulf-1, glycolytic genes, including hexokinase II (HKII) and fructose-2,6-bisphosphatase 3 (PFKFB3), were significantly upregulated compared to control groups. Reintroducing HSulf-1 restored the protein levels of these glycolytic genes, confirming that HSulf-1 downregulation impacts the glycolytic pathway. In terms of glycolytic metabolism, the absence of HSulf-1 leads to a marked increase in glucose uptake, lactic acid secretion, and cellular ATP levels. Glucose uptake experiments revealed that cells lacking HSulf-1 (e.g., Sh1 and Sh2) exhibited enhanced glucose uptake capacity, while HSulf-1-overexpressing cells showed reduced uptake. The loss of HSulf-1 also caused a significant rise in glycolysis-related metabolites, such as glucose-6-phosphate and fructose-1,6-diphosphate. Additionally, HSulf-1 deficiency altered glucose's contribution to the TCA cycle, as evidenced by reduced levels of TCA cycle metabolites like citric acid and fumaric acid. Isotope-labeled glucose tracing experiments further demonstrated that HSulf-1 deletion decreased glucose flux into the TCA cycle and its contribution to cellular energy metabolism. PG545, a compound mimicking HSulf-1's effects, inhibits glucose uptake and lactic acid production caused by HSulf-1 deficiency. By suppressing ERK phosphorylation and c-Myc activation, PG545 reduces the expression of glycolysis-related genes, thereby altering tumor cell metabolic reprogramming. In mouse models, PG545 treatment inhibited tumor growth, as evidenced by reduced tumor volume, fewer metastatic nodules, and increased apoptosis-related markers such as cleaved PARP and caspase-3. These results highlight the potential of targeting HSulf-1-related pathways for cancer therapy (Mondal S et al., 2015).

References

1. Liu N, Yan M, Tao Q, Wu J, Chen J, Chen X, Peng C. "Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis." J Immunother Cancer. 2023 Sep;11(9):e007146. doi: 10.1136/jitc-2023-007146
2. Jo SL, Yang H, Lee SR, Heo JH, Lee HW, Hong EJ. "Curcumae Radix Decreases Neurodegenerative Markers through Glycolysis Decrease and TCA Cycle Activation." Nutrients. 2022 Apr 11;14(8):1587. doi: 10.3390/nu14081587
3. Liu J, Peng Y, Shi L, Wan L, Inuzuka H, Long J, Guo J, Zhang J, Yuan M, Zhang S, Wang X, Gao J, Dai X, Furumoto S, Jia L, Pandolfi PP, Asara JM, Kaelin WG Jr, Liu J, Wei W. "Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res." Erratum in: Cell Res. 2021 Jan;31(1):104. doi: 10.1038/s41422-020-0372-z
4. Kong W, Li T, Li Y, Zhang L, Xie J, Liu X. "Transgenic Cotton Expressing dsAgCYP6CY3 Significantly Delays the Growth and Development of Aphis gossypii by Inhibiting Its Glycolysis and TCA Cycle." Int J Mol Sci. 2024 Dec 31;26(1):264. doi: 10.3390/ijms26010264
5. Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, Ito K, Aoki S. "Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner." Sci Rep. 2019 Dec 10;9(1):18699. doi: 10.1038/s41598-019-55296-3
6. Nie H, Ju H, Fan J, Shi X, Cheng Y, Cang X, Zheng Z, Duan X, Yi W. "O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth." Nat Commun. 2020 Jan 7;11(1):36. doi: 10.1038/s41467-019-13601-8
7. Mondal S, Roy D, Camacho-Pereira J, Khurana A, Chini E, Yang L, Baddour J, Stilles K, Padmabandu S, Leung S, Kalloger S, Gilks B, Lowe V, Dierks T, Hammond E, Dredge K, Nagrath D, Shridhar V. "HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer." Oncotarget. 2015 Oct 20;6(32):33705-19. doi: 10.18632/oncotarget.5605