bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–09–20
sixteen papers selected by
Brett Chrest, Wake Forest University
  1. Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.
  2. The Ketogenic Diet as Adjunctive Strategy in Cancer Treatment-Therapeutic Benefits and Metabolic Risk Using Breast Cancer as an Example.
  3. Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
  4. IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.
  5. Metabolic modulation of glioblastoma by dietary intervention: a systematic review.
  6. The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.
  7. Brief Communication: LSD1 Inhibition Enhances Susceptibility of Primary AML Cells for NK Cell-Mediated Killing.
  8. Direct comparison of serine restriction on the viability of normal and cancer cells demonstrates that methionine restriction is more cancer specific.
  9. Unveiling the oncogenic role of PDK3 in head and neck squamous cell carcinoma, an integrative in silico and an in vitro approach.
  10. Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
  11. Metabolic matching shapes organ-specific metastasis.
  12. Targeting lipid metabolic vulnerabilities with small-molecule inhibitors in acute myeloid leukemia: Emerging insights and therapeutic opportunities.
  13. A fluorescent non-hydrolyzable probe for the nucleotide-binding sites of KATP.
  14. Structure and dynamics of adenosine triphosphate at near-molar concentrations.
  15. Essential mitochondrial activity in Physcomitrium patens relies on complementary cytochrome and alternative oxidase pathways.
  16. Cysteine excess triggers a mitochondrial iron-dependent cell death.
  1. Mol Biol Rep. 2026 Sep 18. pii: 1595. [Epub ahead of print]53(1):
    Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.
    Kaviya S, Sumathy Arockiasamy, K Satish Srinivas, Sundersingh Shirley.
      Metabolic reprogramming is a defining hallmark of CRC. The Warburg effect is the principal metabolic feature of CRC cells, wherein glucose is preferentially catabolized into lactate to sustain accelerated proliferation. In parallel, CRC cells exhibit strong glutamine reliance to replenish tricarboxylic acid (TCA) cycle intermediates required for adenosine triphosphate (ATP) production, lipid biosynthesis and redox homeostasis. Consequently, mitochondria play a central role in supporting the augmented biosynthetic and energetic demands beyond basal energy homeostasis. In this regard, the mitochondrial pyruvate carrier (MPC), mitochondrial citrate carrier (CIC) and the mitochondrial glutamine carrier (SLC1A5_var) located in the inner mitochondrial membrane, are emerging areas of investigation in CRC metabolism. MPC is frequently lost or downregulated in CRC, whereas CIC was found to be upregulated and promote CRC growth and survival. In contrast, SLC1A5_var has been reported to exhibit elevated expression in colon cancer cells. Recent evidence indicates that its inhibition reduces CRC cell viability; however, its specific role in CRC progression remains to be elucidated. Notably, these transporters may influence the metabolic-epigenetic landscape of CRC through metabolite-dependent regulation of chromatin and transcriptional processes. This review highlights current insights into mitochondrial metabolite transporters in CRC and their potential metabolic and epigenetic implications. Thus, elucidating the roles of these transporters may provide novel therapeutic strategies for CRC management.
    Keywords:  Colorectal cancer; Metabolic reprogramming; Warburg effect; epigenetic; glutamine reliance; mitochondrial carriers
    DOI:  https://doi.org/10.1007/s11033-026-12769-9
  2. Nutrients. 2026 Sep 06. pii: 2917. [Epub ahead of print]18(17):
    The Ketogenic Diet as Adjunctive Strategy in Cancer Treatment-Therapeutic Benefits and Metabolic Risk Using Breast Cancer as an Example.
    Jacek Szołtysek, Beata Szymańska, Agnieszka Piwowar.
      Nutritional therapy is an essential component of comprehensive care for cancer patients, playing a vital role in preventing malnutrition, improving treatment tolerance, and maintaining quality of life. In recent years, there has been growing interest in the ketogenic diet as a potential strategy to support cancer therapy. This diet, based on a significant reduction in carbohydrate intake and an increase in fat intake, leads to a state of ketosis that mimics the metabolic changes that occur during starvation. Consequently, the body utilizes ketone bodies as an alternative source of energy. The potential application of the ketogenic diet in oncology stems from the distinct metabolism of cancer cells, which often exhibit an increased demand for glucose. Although the results of preclinical studies suggest a possible anticancer effect of this dietary intervention, clinical evidence remains limited, and its routine use is not currently recommended as a standard of care in oncology. The aim of this study was to analyze the current literature on the use of the ketogenic diet in oncology, with a particular focus on breast cancer. The study assessed the impact of this intervention on metabolic parameters, body composition, and patients' mental well-being, and analyzed the potential metabolic risks associated with its use. The study discusses the molecular basis of oncogenesis and metabolic adaptation in cancer cells, the mechanisms of action of the ketogenic diet, and the results of preclinical and clinical studies as well as meta-analyses. Importantly, the current evidence base should be interpreted with caution. Most mechanistic evidence supporting ketogenic diet in breast cancer derives from preclinical models, whereas clinical studies remain limited by small sample sizes, short intervention periods, heterogeneous ketogenic diet protocols, substantial attrition, and differences in concomitant anticancer treatment. Therefore, mechanistic plausibility and promising preclinical findings should not be interpreted as evidence of clinical anticancer efficacy.
    Keywords:  breast cancer; cancer; ketogenic diet; metabolic risk; quality of life
    DOI:  https://doi.org/10.3390/nu18172917
  3. Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]
    Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
    Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.
      The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.
    Keywords:  GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling
    DOI:  https://doi.org/10.1016/j.cell.2026.08.037
  4. Blood. 2026 Sep 17. pii: blood.2026034181. [Epub ahead of print]
    IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.
    Aykut Demir, Maximilian Mönnig, Nesrine Aroua, Eleni Besiridou, Valentin Schmidt, Kristina Müller, Simon Renders, Fabian Schulte, Alireza Pouya, Alexander Waclawiczek, Aino-Maija Leppä, Karolin Stumpf, Markus Sohn, Dominic Depke, Patrick Wuchter, Darja Karpova, Elisa Donato, Halvard Bonig, Carolin Andresen, Michael Büttner, Gernot Poschet, Daniel Hübschmann, Nicola Zamboni, Tim Sauer, Andreas Trumpp, Carsten Müller-Tidow, Simon Raffel.
      Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance. IDH3 is more abundant in LSCs compared to healthy HSPCs, and TCA cycle activity correlates with inferior clinical outcomes of AML patients. Knockdown of IDH3A, the catalytic subunit of the complex, impairs colony-forming potential and bone marrow organoid as well as in vivo engraftment of AML, while sparing healthy hematopoiesis. Mechanistically, IDH3A downregulation reduces TCA cycle flux and leads to accumulation of intracellular citrate, impairing both glycolysis and oxidative phosphorylation. The resulting bioenergetic crisis activates AMPK and suppresses mTORC1, leading to reduced translational activity and an imbalance of anti-apoptotic proteins. Consequently, IDH3A-KD cells show enhanced susceptibility to BCL2 inhibition by venetoclax in vitro and in vivo. In a clinical cohort, LSCs from patients resistant to venetoclax/azacitidine (Ven/Aza) exhibit transcriptomic programs indicative of active TCA cycle and glycolysis. We demonstrate that downregulation of IDH3A activity and subsequent citrate accumulation directly affect these pathways and shift AML stem cells towards a metabolic state of increased vulnerability. In summary, we establish IDH3 as a metabolic rheostat in LSCs and suggest targeting the IDH3A-citrate axis to overcome Ven/Aza resistance of AML patients.
    DOI:  https://doi.org/10.1182/blood.2026034181
  5. J Neurooncol. 2026 Sep 18. pii: 90. [Epub ahead of print]179(3):
    Metabolic modulation of glioblastoma by dietary intervention: a systematic review.
    Maged T Ghoche, Kenji Miki, Fanen Yuan, Megan Mantica, Sameer Agnihotri, Samuel K McBrayer, Kalil G Abdullah.
       OBJECTIVE: To systematically evaluate and critically synthesize preclinical and clinical evidence on the efficacy, safety, mechanistic rationale, and interpretive limitations of ketogenic diet (KD) and methionine restriction (MR) in glioma treatment.
    METHODS: We systematically searched PubMed and Embase from inception through August 19, 2026, for in vivo preclinical and clinical studies evaluating KD or MR in glioma Clinical studies were eligible with or without a non-diet comparator because most available studies were early-phase, single-arm feasibility investigations. We extracted intervention, comparator, concurrent oncologic treatment, metabolic, safety, feasibility, and outcome data; assessed risk of bias using design-appropriate tools; and conducted narrative and structured direction-of-effect syntheses.
    RESULTS: A total of 43 eligible reports were included: 14 preclinical and 18 clinical KD reports and 9 preclinical and 2 clinical studies of MR. Preclinical effects were heterogeneous: several diet-only experiments reduced growth or prolonged survival, whereas others showed limited activity; selected combinations with radiation, antiangiogenic therapy, glutamine targeting, or immune modulation produced greater effects. Clinical evidence primarily supported feasibility and metabolic activity, not independent efficacy, because most studies were small, uncontrolled, and confounded by concurrent or prior treatment. MR showed preclinical activity, but clinical evidence remained limited to two small chemotherapy-combination trials.
    CONCLUSION: KD and MR have biologic rationale and can alter systemic or intratumoral metabolism, but current clinical data do not establish an independent survival benefit. Their effects cannot be separated reliably from surgery, radiotherapy, chemotherapy, bevacizumab, corticosteroids, and other co-interventions in most studies. Randomized trials with intention-to-treat analysis, standardized glucose-ketone index reporting, treatment and corticosteroid documentation, and longitudinal nutritional assessment are required before these diets can be recommended as effective glioma therapy.
    Keywords:  Dietary intervention; Glioblastoma; Glioma metabolism; Ketogenic diet; Metabolic therapy; Methionine restriction
    DOI:  https://doi.org/10.1007/s11060-026-05779-x
  6. Curr Pharmacol Rep. 2026 ;12(1): 38
    The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.
    Md Salman Shakil, Matthew J McBride.
       Purpose of Review: This article describes the recent discoveries on how the amino acid methionine alters mitochondrial metabolism to support tumor function and growth. A detailed understanding of these mechanisms of cross-talk between the methionine cycle and mitochondria will empower the discovery and development of new metabolism-targeting cancer therapies.
    Recent Findings: Methionine and metabolites of the methionine cycle are increasingly appreciated to have both direct and indirect roles in regulating mitochondrial metabolism, which are critical for survival, growth, and treatment-resistance in tumors. Recent work has discovered multiple mitochondrial transporters that directly connect tumor use of methionine-derived S-adenosylmethionine (SAM) to mitochondrial function. Carnitine is synthesized from SAM-mediated methylation of lysine and is critical for tumor energy generation by fatty acid oxidation. Tumors depend on mitochondrial transport of SAM to support methylation reactions and oxidative phosphorylation. Purine synthesis is supported by mitochondrial one-carbon units from the folate cycle in tumors, which requires remethylation of homocysteine to form methionine to prevent folate trapping. Preclinical and clinical studies investigating both pharmacological and nutritional interventions are uncovering the mechanisms by which mitochondrial function depends on methionine metabolism. Further exploration in this area will define both the targets and specific interventions with the greatest promise for the treatment of cancer patients.
    Summary: Methionine metabolism influences many aspects of mitochondrial function, including energy generation, antioxidant defenses, and lipid composition. Understanding how tumors co-opt these processes and their dependence on the amino acid nutrient methionine provides an opportunity for new cancer therapies.
    Keywords:  Cancer; Metabolism; Methionine; Methylation; Mitochondria; S-adenosylmethionine
    DOI:  https://doi.org/10.1007/s40495-026-00481-y
  7. J Immunother. 2026 Sep 14.
    Brief Communication: LSD1 Inhibition Enhances Susceptibility of Primary AML Cells for NK Cell-Mediated Killing.
    Mohammadamin Sookhaklari, Adnan Moinuddin, Kanwaldeep Singh, M Talha Yuksel, Misaal Mehboob, Fatemeh Vahedi, Ali A Ashkar, Tobias Berg.
      Acute myeloid leukemia (AML) is a hematological malignancy associated with poor prognosis. Recent developments in natural killer (NK) cell-based immunotherapies have resulted in the robust expansion of NK cells with enhanced cytotoxicity against hematological malignancies. However, disease relapse remains a challenge. Another therapeutic intervention that has garnered high interest is the use of lysine-specific demethylase 1 (LSD1) inhibitors for AML treatment. Here, we investigated whether LSD1 inhibition could synergize with ex vivo expanded NK (exNK) cells in a primary AML sample. Interestingly, we observed that treatment with the LSD1 inhibitors, bomedemstat and GSK-LSD1, led to the upregulation of multiple stress ligands known to activate NK cells. Importantly, this increased stress ligand expression was associated with enhanced NK cell-mediated cytotoxicity, suggesting the potential for both therapies to be used synergistically. To our knowledge, this is the first study to assess the combination of LSD1 inhibition and exNK cells in AML.
    Keywords:  LSD1 inhibition; NK cell immunotherapy; acute myeloid leukemia; natural killer cells
    DOI:  https://doi.org/10.1097/CJI.0000000000000618
  8. Front Oncol. 2026 ;16 1931323
    Direct comparison of serine restriction on the viability of normal and cancer cells demonstrates that methionine restriction is more cancer specific.
    Yuta Miyashi, Tomoyuki Ishiguro, Qinghong Han, Shukuan Li, Byung Mo Kang, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.
       Background/aim: Many studies in the present century have stated that restriction of serine is a cancer-specific vulnerability. The present study aimed to determine whether restriction of serine, compared to restriction of methionine, distinguishes cancer and normal cells.
    Materials and methods: 143B-RFP osteosarcoma cells, HT1080-RFP fibrosarcoma cells, HCT116-GFP colon-cancer cells, and Hs27 normal fibroblasts were used in the present study. All cells are of human origin. Cancer and normal cells were cultured in RPMI-1640 medium without serine and glycine for serine/glycine restriction, and in Dulbecco's modified Eagle's medium without methionine for methionine restriction, each supplemented with 10% dialyzed fetal bovine serum. Cancer and normal cells were cultured in 96-well plates at 2 × 103 cells/well. Serine, glycine, and methionine were added back as controls. Cell viability was measured with the WST-8 cell-viability reagent to establish dose-response curves for serine (with or without glycine) and for methionine in cancer and normal cells. Each cancer cell line was also co-cultured with Hs27 normal fibroblasts in 12-well plates. Each cell type was evaluated by phase-contrast and GFP/RFP fluorescence microscopy to determine the effects of serine/glycine restriction or methionine restriction.
    Results: Serine restriction alone did not distinguish cancer and normal cells. Both 143B osteosarcoma and Hs27 normal fibroblasts maintained approximately 100% viability without serine in glycine-containing medium. The HT1080-RFP and HCT116-GFP cancer cells lost approximately 40% of their viability without serine and showed increasing viability with increasing serine concentration. When both serine and glycine were restricted, Hs27 fibroblasts lost approximately 20% viability, whereas all cancer cells lost about 40% viability. Neither serine restriction nor serine/glycine restriction could lower the viability of cancer cells to 50% of control. In co-culture, the removal of serine and glycine still left many cancer cells viable. In contrast, methionine removal caused a much greater reduction in cancer-cell viability than removal of serine/glycine. Hs27 normal fibroblasts survived well under both serine/glycine and methionine restriction.
    Conclusion: Serine restriction and serine/glycine restriction are not as cancer-specific as methionine restriction.
    Keywords:  Hoffman effect; cancer; cancer cells; co-culture; glycine; methionine restriction; normal fibroblasts; serine
    DOI:  https://doi.org/10.3389/fonc.2026.1931323
  9. J Genet Eng Biotechnol. 2026 Sep;pii: S1687-157X(26)00112-5. [Epub ahead of print]24(3): 100768
    Unveiling the oncogenic role of PDK3 in head and neck squamous cell carcinoma, an integrative in silico and an in vitro approach.
    Aishath Shaheeda, Dharini N Shetty, Padmanaban S Suresh, Roshan Mascarenhas, Kabekkodu Shama Prasada.
      Head and neck squamous cell carcinoma (HNSCC) is a clinically aggressive malignancy with a poor prognosis. Emerging evidence highlights the importance of metabolic reprogramming in tumor progression and therapy resistance. However, the mechanisms driving metabolic adaptation in HNSCC remain incompletely understood. Here, we investigate pyruvate dehydrogenase kinase 3 (PDK3), a regulatory enzyme critical for aerobic glycolysis (the Warburg effect) in cancer cells. Using computational analysis and experimental validation, we explored PDK3's role as an oncogene in HNSCC. Our gene expression analysis revealed that PDK3 is significantly upregulated in tumors compared to normal tissues. Pathway enrichment analysis linked PDK3 to key metabolic pathways essential for cellular energy production and biosynthesis, including the TCA cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. Additionally, PDK3 upregulation influenced immune cell distribution and drug response. Clinically, elevated PDK3 expression correlated with reduced overall survival in patients. Functional validation in an HNSCC cell line (HSC3) demonstrated that PDK3 knockdown suppressed growth, proliferation, and migration, suggesting PDK3's role as a potential tumor promoter in HNSCC. These findings indicate that targeting PDK3 could be a promising therapeutic strategy for HNSCC management.
    Keywords:  Gene expression analysis; HNSCC; Metabolic modeling; PDK3; Pathway enrichment; Survival prognosis
    DOI:  https://doi.org/10.1016/j.jgeb.2026.100768
  10. Nat Commun. 2026 Aug 15. pii: 9829. [Epub ahead of print]17(1):
    Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
    Hyunmin Cho, Ruhi Sayana, Abhishek Koladiya, Pasqualina Colella, Sangkyun Cho, James W S Jahng, Juan Jose Vasquez, Jessica Arozqueta Basurto, Joseph C Wu, Natalia Gomez-Ospina.
      Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-026-76775-y
  11. Biochim Biophys Acta Rev Cancer. 2026 Sep 14. pii: S0304-419X(26)00177-0. [Epub ahead of print]1881(6): 189705
    Metabolic matching shapes organ-specific metastasis.
    Cristina Álvarez-Álvarez, Patricia Altea-Manzano.
      Metastasis is the leading cause of cancer-related mortality, yet the mechanisms driving organ-specific colonization remain incompletely understood. Increasing evidence suggests that metastatic success depends on a "metabolic match" between disseminated tumor cells and the microenvironment of the target organ. In this mini-review, we discuss how intrinsic metabolic programs inherited from the primary tumor interact with extrinsic factors such as nutrient availability, redox balance, extracellular matrix remodeling, and organ-resident cells to shape metastatic organotropism. We propose that the interplay between cancer cell metabolic plasticity and tissue-specific metabolic landscapes critically determines metastatic fitness and may uncover new therapeutic vulnerabilities.
    Keywords:  Metabolic match; Metabolic plasticity; Metastasis; Metastatic organotropism; Organ-resident cells; Pre-metastatic niche; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189705
  12. Tzu Chi Med J. 2026 Oct-Dec;38(4):38(4): 434-445
    Targeting lipid metabolic vulnerabilities with small-molecule inhibitors in acute myeloid leukemia: Emerging insights and therapeutic opportunities.
    Jui-Hung Yen, Trung Q Phan, Je-Wen Liou, Pei-Yi Chen.
      Metabolic reprogramming has recently been recognized as a hallmark of cancer. In acute myeloid leukemia (AML), clinically relevant metabolism-targeted therapies have primarily focused on inhibiting mitochondrial energy production; however, their clinical progress has been limited by substantial and nonspecific toxicity. Emerging evidence indicates that reprogramming of lipid metabolism represents a defining feature of leukemic transformation. Lipids not only serve as fundamental structural components of cellular membranes but also function as key signaling molecules and energy sources. In AML cells, lipid uptake, storage, and de novo synthesis are markedly increased, thereby supporting rapid proliferation, survival, and leukemic progression. Consequently, dysregulated lipid metabolism has attracted growing attention as a promising therapeutic vulnerability in AML. This review summarizes the conceptual framework underlying AML cell dependence on cholesterol, fatty acids (FAs), sphingolipids, and broader lipid metabolic pathways. We highlight recent advances in understanding aberrant lipid metabolic programs in AML, including alterations in cholesterol biosynthesis, FA uptake and lipogenesis, FA oxidation, and sphingolipid metabolism. Particular emphasis is placed on the regulatory mechanisms that maintain lipid metabolic homeostasis and how their disruption contributes to leukemogenesis and therapy resistance. Furthermore, we discuss emerging therapeutic strategies aimed at targeting lipid metabolic pathways, with a focus on small-molecule inhibitors that selectively interfere with lipid metabolism-associated enzymes and signaling networks. By delineating key molecular targets and their pharmacological inhibitors, this review highlights the potential of lipid metabolism-based interventions as innovative and effective treatment strategies for AML.
    Keywords:  Acute myeloid leukemia; Fatty acid oxidation; Lipid metabolism; Metabolic reprogramming; Small-molecule inhibitors
    DOI:  https://doi.org/10.4103/tcmj.TCMJ-D-26-00039
  13. J Gen Physiol. 2026 Nov 02. pii: e202513840. [Epub ahead of print]158(6):
    A fluorescent non-hydrolyzable probe for the nucleotide-binding sites of KATP.
    Priscilla Rubio, Shayla Q Whitaker, Jonathan Ashby, Michael C Puljung.
      Neuroendocrine ATP-sensitive K+ channels (KATP) comprise four pore-forming subunits (Kir6.2), each associated with a modulatory sulfonylurea receptor subunit (SUR1). ATP/ADP binding to Kir6.2 inhibits KATP; MgATP/MgADP binding to two different sites on SUR1 promotes activation. As SUR1 is a member of the ABC transporter family of proteins, it can potentially hydrolyze MgATP to MgADP. Whether this activity is required for KATP activation remains controversial. Previous studies demonstrated that non-hydrolyzable ATP analogs do not activate KATP, which may reflect an inability of these compounds to bind to SUR1, their inability to promote a conformational change in SUR1 that leads to channel activation, or a requirement for ATP hydrolysis during channel gating. To explore this further, we synthesized a fluorescent trinitrophenyl (TNP) derivative of the non-hydrolyzable ATP analog β,γ-methyleneadenosine 5'-triphosphate (AMP-PCP). Synthesis was verified by UV-visible absorbance, fluorescence spectroscopy, 1H NMR, and mass spectrometry. Purity was assessed by reversed-phase HPLC. Real-time nucleotide binding to intact KATP channels in cell membranes was measured using FRET between channels labeled with a fluorescent, noncanonical amino acid and TNP-nucleotide derivatives. This technique provides sufficient spatial resolution to discriminate between binding to each site on KATP. Using this approach, we first established that TNP-ATP can bind to nucleotide-binding site (NBS) 1 on SUR1 in fluorescently labeled Kir6.2/SUR1 channels in unroofed membranes of HEK293T cells. We subsequently demonstrated that TNP-AMP-PCP binds to both NBSs on SUR1 in the absence of Mg2+. AMP-PCP was able to compete with TNP-ATP for binding to NBS2, suggesting that it, too, binds NBS2. We conclude that the failure of non-hydrolyzable ATP analogs to activate KATP does not stem from an inability of these nucleotides to bind to the channel.
    DOI:  https://doi.org/10.1085/jgp.202513840
  14. Biophys Chem. 2026 Sep 03. pii: S0301-4622(26)00144-4. [Epub ahead of print]340 107711
    Structure and dynamics of adenosine triphosphate at near-molar concentrations.
    Songzhu Luo, Zihan Li, Choon-Peng Chng, Changjin Huang, Chun Tang, Kai Xue.
      Adenosine-5'-triphosphate (ATP) can accumulate to near-molar concentrations within specific biological compartments, influencing a diverse range of cellular processes. However, its structural organization and molecular dynamics under these crowded conditions remain poorly understood. In this study, ATP gel systems containing ATP at near-molar concentrations were prepared and investigated using solid-state nuclear magnetic resonance (ssNMR) spectroscopy and all-atom molecular dynamics (MD) simulations. The ssNMR results reveal that ATP undergoes spontaneous hydrolysis and yields adenosine diphosphate (ADP) and inorganic phosphate (Pi). Combined ssNMR and MD analyses further suggest local purine-stacked and ion-mediated "tail-to-tail" arrangements of ATP/ADP molecules, in which cationic clusters attract anionic phosphate groups and restrict terminal phosphate mobility. The suppression of ATP β-phosphate signals is attributed to reduced hydration arising from steric hindrance and limited solvent accessibility. A comparison of ATP-HCl and ATP-HAc gels demonstrates that both ATP hydrolysis level and molecular dynamics are strongly modulated by anion identity. MD simulations further reveal a modest increase in Mg2+-mediated intermolecular bridging and a slightly higher local mass density in ATP-HCl gels. These results provide molecular-level insight into ATP behavior at high concentrations and highlight the critical role of anion species in regulating ATP stability and organization.
    Keywords:  Adenosine triphosphate; Molecular dynamics; Near-molar concentration; Solid-state NMR spectroscopy
    DOI:  https://doi.org/10.1016/j.bpc.2026.107711
  15. Plant J. 2026 Sep;127(5): e71127
    Essential mitochondrial activity in Physcomitrium patens relies on complementary cytochrome and alternative oxidase pathways.
    Shun-Ling Tan, Antoni M Vera-Vives, Heyu Wang, Xing Huang, Claudia Beraldo, Alessandro Alboresi, Tomas Morosinotto.
      Mitochondrial respiration catalyses the transfer of electrons from NADH to oxygen through the activity of five multiprotein complexes. In plants, mitochondria also possess additional alternative electron transport pathways, including the alternative oxidase (AOX) pathway, which transfers electrons from ubiquinol to O2, bypassing the cytochrome-dependent electron transport chain. This study investigates the functional role of AOX during plant evolution by analysing Physcomitrium patens plants that lack or overexpress AOX. In the moss P. patens, AOX exhibits a remarkably high electron transport capacity, sufficient to fully compensate for the inactivation of the cytochrome pathway. Despite the high potential activity of AOX, aox knockout lines did not show significant defects in growth under various abiotic stresses. This suggests that the cytochrome pathway can compensate for AOX loss and effectively support the consumption of reducing power produced by photosynthesis even under stressful conditions. Although photosynthetically active cells can produce ATP in chloroplasts under illumination independently of mitochondrial electron transport, respiration is shown to be essential for the conversion of reducing power into ATP for distribution throughout the cell. Simultaneous inactivation of AOX and CIII was lethal, indicating that AOX and the complementary cytochrome pathway contribute to the essential role of mitochondrial respiration in the redox and energy balance in P. patens cells.
    Keywords:  AOX; ATP; Physcomitrium patens; cytochrome pathway; photosynthesis
    DOI:  https://doi.org/10.1111/tpj.71127
  16. Nat Metab. 2026 Sep 15.
    Cysteine excess triggers a mitochondrial iron-dependent cell death.
    Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.
      Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.
    DOI:  https://doi.org/10.1038/s42255-026-01616-7
This page is being maintained by Thomas Krichel. It was last updated on 2026‒09‒20 at 14:50.