ALPHA KETOGLUTARATE

Analysis of patient data from large scale immunotherapy trials including melanoma and clear cell kidney cancer shows higher patient levels of alpha ketoglutarate (AKG) lead to much better treatment responses. AKG is a naturally circulating kind of keto-acid, and commonly available supplement sometimes called 2-oxoglutarate, popular in anti-aging science. Its produced by enzymes breaking down foods including dairy. In particular, AKG can help improve or rejuvenate mitochondrial health, and target uses include long term kidney, muscle, skin and tissue health. In cancer, AKG is emerging in lab trials as compound increasing responses during immunotherapy in particular, but potentially radio and chemotherapies too

Recent pre-clinical study reports higher immunotherapy response are found in melanoma patients with higher αKG levels. Compelling in-vivo testing confims that boosting levels during PD-1 therapy significantly increase response rates and disease free survival – nivolumab, pembrolizumab and more. The AKG enhanced immune response via interferon gamma INFγ-STAT1/3 signaling is explained, a process also seen in lung cancer progression. Very similar finding have been made in lymphoma and clear cell kidney cancer (see References). Pre-clinical work uses DMKG, an αKG derivative used in research studies which can penetrate cells directly. For instance, amplifying radiotherapy outcomes, reducing TNBC treatment evasion utilizing the burst in autophagy bought on by radation.

Both with immunotherapy and radiotherapy, lab results show increasing levels break down tumor resistance to treatment. AKG is metabolized quickly and effects are sustained at least a day. Some of the studies show tumor growth suppression by AKG alone, and suggest likely improvement in chemotherapy. And other pre-clinical studies strongly suggest anti-metastatic activity, which is yet to be proven in clinical trials. Whats important here is to ramp up and sustain alpha ketoglutarate before and during immunotherapy.

There are fascinating ongoing clinicial trials into the health and lifespan extending actions of AKG, based on its ability to re-regulate mitochondrial health. Research also shows that when glucose restriction drugs are used to suppress tumor growth, low levels of AKG result. And this drives mutation to more aggressive and resistant behaviors which have been observed when glucose inhibitors are removed during trials on pancreatic cancer. Future research may expand on how to optimize the use of several drugs and compounds.

TYPICAL ABSORPTION LEVELS

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EXAMPLES OF IMPROVED OUTCOMES

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PRE-DIAGNOSIS OR PREVENTION

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Highlighted Studies

..supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter…..analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a nove...

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Elevated levels of αKG [in kidney cancer tumors] promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone… Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms ...

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To further explore the functional mechanisms of α-KG in DLBCL [lymphoma], we performed RNA-sequencing in DM-αKG-treated DLBCL cells…..DM-αKG treatment promoted ROS release and lipid peroxidation, followed by impaired ATP production and decreased mitochondrial pathway expression. Moreover, differentially expressed genes analysis identified an increased expression of TP53 in the ferroptosis pathway, indicating the importance of TP53 in α-KG-induced ferroptosis…..Our present find...

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In summary, our findings propose that the supplementation of alpha-ketoglutarate (AKG) augments radiotherapy sensitization and ameliorates the tumor immune microenvironment [TNBC]. This could be associated with the inhibition of autophagy and the stimulation of inflammatory cytokine release. Owing to its robust biosafety profile, DMKG presents promising prospects for clinical translation, potentially enhancing radiotherapy sensitivity and improving the outcomes of immunotherapy.

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TABLE OF REFERENCES

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https://www.nature.com/articles/s41419-023-05692-53.5Human study, Lab study- adjunct Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.Moreover, α-KG has a low extraction cost and good stability when dissolved in water [48], which has great potential for clinical applications. In summary, our findings confirmed that α-KG enhanced the immunotherapeutic efficacy of anti-PD1 through the TET2/3-STAT1/3-CD274 pathway and that supplementation with α-KG plus treatment with anti-PD1 might be a novel strategy for melanoma treatment.Moreover, α-KG has a low extraction cost and good stability when dissolved in water [48], which has great potential for clinical applications. In summary, our findings confirmed that α-KG enhanced the immunotherapeutic efficacy of anti-PD1 through the TET2/3-STAT1/3-CD274 pathway and that supplementation with α-KG plus treatment with anti-PD1 might be a novel strategy for melanoma treatment.Screenshot from 2025-06-24 11-12-03
https://onlinelibrary.wiley.com/doi/full/10.1002/advs.2023019753.5Lab study- adjunct Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.Therapy with anti-PD-1 antibody or αKG treatment alone both inhibited tumor growth in two respective murine models, while combination therapy of anti-PD-1 antibody and αKG treatment further delayed tumor growth or even led to tumor regression (Figure 7C,D) and significantly increased overall survival compared with monotherapy (Figure 7E,F). Furthermore, the proportions of intratumoral CD8+ T cells were significantly increased in the combination group (Figure 7G). To confirm the importance of CD8+ T cells in the combination group, we depleted CD8+ T cells after tumor transplantation and observed rapid re-progression of the tumor (Figure 7H), indicating the critical role of CD8+ T cells in the significant anti-tumor effects produced by combination treatment of αKG and anti-PD1.Screenshot from 2025-06-24 11-14-03
https://onlinelibrary.wiley.com/doi/10.1002/hon.3164_1653Untargeted metabolomics profiling revealed that the metabolic characteristics of DLBCL patients were significantly different from healthy controls. Among the differentially expressed metabolic pathways, glutamine metabolism accounted for the highest weight, suggesting the importance of glutamine metabolism in the tumorigenesis of DLBCL (Figure 1A). Notably, glutamate, glutamine, and α-KG were the critical metabolites in glutamine metabolism. Clinical data analysis identified that high glutamine concentrations and low decreased α-KG were associated with poor prognosis in DLBCL patientsDM-αKG induced non-apoptotic cell death phenotypes, represented by cell membrane swelling and LDH release. To further explore the functional mechanisms of α-KG in DLBCL, we performed RNA-sequencing in DM-αKG-treated DLBCL cells. As shown in enrichment analysis, DM-αKG treatment showed apparent dysfunction in the hypoxia-inducible factor pathway, oxidative stress response, and ferroptosis (Figure 1C). In particular, DM-αKG treatment promoted ROS release and lipid peroxidation, followed by impaired ATP production and decreased mitochondrial pathway expression. Moreover, differentially expressed genes analysis identified an increased expression of TP53 in the ferroptosis pathway, indicating the importance of TP53 in α-KG-induced ferroptosisScreenshot from 2025-06-24 11-15-18
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04312-23Lab studyOur study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy.DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment.
https://www.mdpi.com/2076-3921/10/11/18042.5Lab studyOur data demonstrated that the combined solution of aKG + 5-HMF (1:3) showed an anti-proliferative impact on Jurkat cells in lowering mitochondrial-activity, increasing caspase-3-activity and apoptosis-inducing effects in Jurkat cells, which seems to be related to its antioxidative potential. However, no negative effect was obtained on HF-SAR in cell proliferation, whereas the mitochondrial activity was positively influenced. These results may thus provide a basis for further studies on cancer cells and on the individual compounds.Here, AKG + 5-HMF showed great potential for decreasing the mitochondrial activity in Jurkat cells and, therefore, their proliferation. No mitochondrial activity effects were found in HF-SAR cells using aKG + 5-HMF, but a slight increase of cell proliferation was obtained using 500 µg/mL aKG + 166.7 µg/mL 5-HMF for 72 h combined with a reduction of carbonylated proteins in HF-SAR lysed cells. The experiments with on HF-SAR indicated that there were no cancerogenic effects of aKG and 5-HMF on normal healthy cells.
https://ashpublications.org/blood/article/140/Supplement%201/2046/490416/Alpha-Ketoglutarate-Suppresses-MYC-and-mTORC1-and2.5We found that αKG induced a rapid decrease in MYC protein expression, which was blocked by proteasome inhibitors.......We concluded that αKG via inhibition of at least two oncogenic nodes, MYC and mTORC1, displays anti-lymphoma properties in vitro and in vivo. This discovery has concrete paths for clinical translational as dietary supplementation of αKG was shown to counter inflammation and increased longevity in mice (Shahmirzadi et al, Cell Metab 2020), a result that has spearhead human clinical trialsWe next tested the anti-lymphoma activity of αKG in vivo. First, we used an adoptive transfer assay of Eµ-Myc-derived B cell lymphoma. In two independently cohorts (n=30), we examined tumor burden and survival as primary endpoints. Tumor burden was significantly suppressed in the αKG arm (lymph node weights 11mg vs. 21mg) and, in a second cohort, mice in the αKG arm lived significantly longer (median survival = not reached vs. 42 days in the control). Lastly, in 3 independent cohorts of xenograft models of human DLBCLs, αKG .. significantly inhibited subcutaneous tumor growth
https://aacrjournals.org/cancerres/article/82/13/2388/705041/Targeting-BCAT1-Combined-with-Ketoglutarate2Gabapentin is an FDA-approved antiepileptic drug. Our studies reveal its new potential application for a combination therapy with AKG in combating IDHWT GBM. This combined approach shows the killing effect specifically on IDHWT GBM cells but not normal astrocytes, suggesting that BCAT1i/AKG combination is a nontoxic therapeutic strategy that can be translated into the clinical investigation in patients with IDHWT GBMIn conclusion, we identified BCAT1i/AKG combination as a new synthetic lethal approach in IDHWT GBM. BCAT1i/AKG combination causes mitochondrial dysfunction and depletes the fundamental cellular building blocks including ATP, nucleotides, and proteins, leading to death of IDHWT GBM cells
https://www.nature.com/articles/s41420-024-01805-x2In conclusion, the present study describes the synergistic effect of αKG supplementation in combination with SLC25A1 inhibition on cellular and mitochondrial function, creating a cellular demand for NAD to balance cellular activities important for cancer cell survival and radiosensitization. Furthermore, our results provide a new angle for understanding the novel context-dependent role of αKG in the cancer progression and the treatment of cancerJIB-04 treatment was proposed for use in clinical trials because it altered transcriptional growth programs in cancer cells but not in normal cells, resulting in the induction of cancer-specific cell death induction [53, 54]. Consistent with the reported results, JIB-04 treatment increased the level of cell death and reduced cell proliferation, with or without IR in the present study. Notably, the antineoplastic effect of JIB-04 treatment recapitulated the phenotype induced by CTPI2 treatment and was significantly enhanced by αKG supplementation, consistent with the results obtained with CTPI2 treatment.
https://www.nature.com/articles/s43018-020-0035-52e found that αKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using organoids derived from patients with CRC and several in vivo CRC tumor models, we show that αKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumor growth and extending survival. Together, our results reveal how the metabolic microenvironment impacts Wnt signaling and identify αKG as a potent antineoplastic metabolite for potential differentiation therapy for patients with CRC.Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumorigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC-mutant intestinal organoids to promote stemness, and leads to adenocarcinoma formation in vivo via decreasing intracellular α-ketoglutarate (αKG) levels. αKG supplementation is sufficient to rescue low-glutamine-induced stemness and Wnt hyperactivation.
https://aacrjournals.org/cancerres/article/84/2/305/733107/Glucose-Deprivation-Promotes-Pseudohypoxia-and1.5Here, we show that glucose deprivation in LUAD causes cancer dedifferentiation similar to that caused by glutamine restriction. Glucose deprivation reduces αKG availability, limiting αKG-dependent histone demethylase activity, and induces histone hypermethylation, driving LUAD to a poorly differentiated state and a highly aggressive phenotype. Surprisingly, we found that glucose restriction-induced dedifferentiation and increased aggressiveness require activation of the hypoxia-inducible factor 1α (HIF1α) signaling. EZH2 is involved in upregulation of HIF1α by direct repression of the proline hydroxylase PHD3, which initiates HIF1α degradation in normoxia. HIF1α induces Slug activity and epithelial-to-mesenchymal transition (EMT), leading to a highly aggressive and metastatic phenotype. Combination treatments with epigenetic modulators or HIF inhibitors are therefore important strategies as metabolic therapies are moved to the clinic. The challenge will be to find the right therapeutic window to prevent starvation-induced dedifferentiation without causing significant side effects due to whole-body inhibition of H3K27 methylation. In the future, alternative strategies to increase the intracellular αKG levels (inhibition of oxoglutarate dehydrogenase, direct supplementation of αKG) may also be implemented to prevent starvation-induced dedifferentiation
https://www.sciencedirect.com/science/article/pii/S108495211830171X1.5In the last two decade, metabolomics studies have shown a hub role of αKG in the metabolic reprogramming required for cancer cells survival and proliferation. In addition, as allosteric activator of PHDs αKG is a pivotal regulator of the hypoxic response and epigenetic modifications, two major drivers of oncogenic transformation. This scenario opens the opportunity to exploit the multifaceted contribution of αKG on metabolic rewiring and hypoxic adaptations as a potential adjuvant therapeutic strategy to impinge on tumor progressionMost importantly, it constitutes the rate-limiting substrate of 2-oxoglutarate-dependent dioxygenases family enzymes, which are involved in hypoxia sensing and in the shaping of cellular epigenetic landscape, two major drivers of oncogenic transformation. Based on literature reports, we hereby review the benefits of this metabolite as a possible novel adjuvant therapeutic opportunity to target tumor progression. This article is part of the special issue “Mitochondrial metabolic alterations in cancer cells and related therapeutic targets”.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289018/1.5 Nevertheless, α-KG supplementation leads to the risk of feeding oncogenic pathways not only due to its conversion into (L)-2-HG in respiratory deficient cells but also into succinate and fumarate, on a long-term treatment [137]. On the other hand, several human Fe(II)/α-KG-dependent dioxygenases have been investigated as possible therapeutic targets and might represent an interesting alternative strategy to render tumors more sensitive to radiotherapy and chemotherapy [90]. A complete understanding of the α-KG-mediated interplay between metabolic and genetic reprogramming will help us to disclose a new therapeutic window in which cancer progression can be restrainedα-ketoglutarate was shown to withstand a wide range of physiological reactions from protection against oxidative stress, collagen and bone maintenance to development and immunity. Most importantly, it constitutes the rate-limiting substrate of 2-oxoglutarate-dependent dioxygenases family enzymes, which are involved in hypoxia sensing and in the shaping of cellular epigenetic landscape, two major drivers of oncogenic transformation. Based on literature reports, we hereby review the benefits of this metabolite as a possible novel adjuvant therapeutic opportunity to target tumor progression
https://pubmed.ncbi.nlm.nih.gov/29599405/1Lab studyReduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy. Our results showed that the combinations of oxythiamine with docetaxel and doxorubicin had maximum inhibitory effects in TNBC cells, suggesting combinatory drug treatment as a novel therapy against TNBC. Our study for the first time revealed that oxythiamine treatment elevated the levels of αKG in TNBC cells, suggesting that oxythiamine suppressed tumor cell growth via αKG signaling pathway. Together, it is feasible to develop a combinatory drug treatment with the conventional therapeutic drugs to improve treatment benefits for TNBC

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