bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–01–18
nine papers selected by
Brett Chrest, Wake Forest University
  1. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  2. Language model-guided anticipation and discovery of mammalian metabolites.
  3. Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
  4. Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
  5. Improved flux profiling in genome-scale modeling of human cell metabolism.
  6. Potassium ion homeostasis modulates mitochondrial function.
  7. Intermittent fasting enhances cisplatin-metformin efficacy in therapy-resistant ovarian cancer PDXs.
  8. FLIPs: Genetically encoded molecular biosensors for functional imaging of cell signaling by linear dichroism microscopy.
  9. Antileukemic therapies for older adults with AML ineligible for conventional therapy: systematic review & meta-analysis.
  1. Nat Metab. 2026 Jan 16.
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.
      Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.
    DOI:  https://doi.org/10.1038/s42255-025-01428-1
  2. Nature. 2026 Jan 14.
    Language model-guided anticipation and discovery of mammalian metabolites.
    Hantao Qiang, Fei Wang, Wenyun Lu, Xi Xing, Hahn Kim, Sandrine A M Mérette, Lucas B Ayres, Eponine Oler, Jenna E AbuSalim, Asael Roichman, Michael Neinast, Ricardo A Cordova, Won Dong Lee, Ehud Herbst, Vishu Gupta, Samuel L Neff, Mickel Hiebert-Giesbrecht, Adamo Young, Vasuk Gautam, Siyang Tian, Bo Wang, Hannes Röst, Jatinder Baidwan, Russell Greiner, Li Chen, Chad W Johnston, Leonard J Foster, Aaron M Shapiro, David S Wishart, Joshua D Rabinowitz, Michael A Skinnider.
      Despite decades of study, large parts of the mammalian metabolome remain unexplored1. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks in human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains challenging2-4. Biochemical language models have transformed the interpretation of DNA, RNA and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here we present an approach that leverages chemical language models5-7 to anticipate the existence of previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns from the structures of known metabolites to anticipate the existence of previously unrecognized metabolites. Integration of DeepMet with mass spectrometry-based metabolomics data facilitates metabolite discovery. We harness DeepMet to reveal several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to advance the mapping of the mammalian metabolome.
    DOI:  https://doi.org/10.1038/s41586-025-09969-x
  3. J Inherit Metab Dis. 2026 Jan;49(1): e70142
    Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
    Karin Terburgh, Nastassja Sweeney, Roan Louw.
      The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, 1H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.
    Keywords:  Leigh syndrome; Ndufs4 knockout mice; complex I deficiency; heart metabolism
    DOI:  https://doi.org/10.1002/jimd.70142
  4. Exp Hematol. 2026 Jan 12. pii: S0301-472X(26)00012-3. [Epub ahead of print] 105379
    Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
    Reecha Shah, Nathan Kingston, Giulia Fabbri, Jamal Saeh, Courtney Andersen, Patricia Cheung.
      Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the anti-apoptotic protein B-cell lymphoma 2 (BCL-2) for survival.1 Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly AML patients. BCL-XL, another pro-survival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax.2 Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL.3 This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the anti-leukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMA) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in AML patient-derived xenograft models with prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in AML patients, particularly, those who do not respond to venetoclax.
    Keywords:  AZD0466; Acute Myeloid Leukemia; Apoptosis; BCL-2/BCL-XL inhibitor; BH3 mimetic; Combination Treatment; Targeted therapy
    DOI:  https://doi.org/10.1016/j.exphem.2026.105379
  5. Cell Rep Methods. 2026 Jan 12. pii: S2667-2375(25)00311-X. [Epub ahead of print] 101275
    Improved flux profiling in genome-scale modeling of human cell metabolism.
    Cyriel A M Huijer, Xiang Jiao, Yun Chen, Rosemary Yu.
      Understanding human cell metabolism through genome-scale flux profiling is of interest to diverse research areas of human health and disease. Metabolic modeling using genome-scale metabolic models (GEMs) has the potential to achieve this, but has been limited by a lack of appropriate input data as model constraints. Here, we compare the commonly used consumption and release (CORE) method to a regression-based method (regression during exponential growth phase; REGP). We found that the CORE method is not reliable despite being prevalent in human studies, whereas the exchange fluxes determined by REGP provide constraints that substantially improve GEM simulations for human cell lines. Our results show that the GEM-simulated feasible flux space is constrained to a biologically plausible region, allowing an exploration of the basic organizing principles of the feasible flux space. These improvements help to fulfill the promise of GEMs as a valuable tool in the study of human metabolism and future development of translational applications.
    Keywords:  CP: metabolism; CP: systems biology; cell metabolism; feasible flux space; flux profiling; genome-scale metabolic modeling
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101275
  6. J Cell Biol. 2026 Apr 06. pii: e202505110. [Epub ahead of print]225(4):
    Potassium ion homeostasis modulates mitochondrial function.
    Adam James Waite, Beiduo Rao, Elizabeth Schinski, Nathaniel H Thayer, Manuel Hotz, Austin E Y T Lefebvre, Celeste Sandoval, Daniel E Gottschling.
      Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.
    DOI:  https://doi.org/10.1083/jcb.202505110
  7. iScience. 2026 Jan 16. 29(1): 114300
    Intermittent fasting enhances cisplatin-metformin efficacy in therapy-resistant ovarian cancer PDXs.
    Elena Capellini, Ludovica Perotti, Federica Guffanti, Giulia De Simone, Aurelia Morabito, Anna Maria Ronchi, Laura Sala, Eugenio Scanziani, Daniela Corna, Domenico Cerullo, Cristina Matteo, Robert Fruscio, Laura Brunelli, Giovanna Damia, Francesca Ricci.
      The development of platinum resistance is a significant challenge in the management of ovarian cancer. Targeting the metabolic adaptability of cancer cells and combining dietary interventions with pharmacological treatments are emerging strategies in oncology, enhancing therapy efficacy at low costs. Using ovarian cancer cisplatin-resistant patient-derived xenografts, we showed that repeated cycles of cisplatin plus metformin reversed platinum resistance by remodeling tumor metabolism. Then, based on metabolomic studies, we explored the use of different food approaches, in particular diets with a high vs. a low methionine content and the intermittent fasting regimen, to further stress tumor metabolism and increase the effect of drug treatment. Our findings demonstrated that only intermittent fasting enhanced the antitumor effects of the drug combination and significantly improved the survival, by impairing the tumor energy states. This research highlights the potential of integrating diet-based approaches with pharmacological treatments to overcome platinum resistance in ovarian cancer.
    Keywords:  cancer; diet; therapeutics
    DOI:  https://doi.org/10.1016/j.isci.2025.114300
  8. Sci Adv. 2026 Jan 16. 12(3): eadz5662
    FLIPs: Genetically encoded molecular biosensors for functional imaging of cell signaling by linear dichroism microscopy.
    Paul Miclea, Vendula Nagy-Marková, Robin Van den Eynde, Wim Vandenberg, Alina Sakhi, Alexey Bondar, Jitka Myšková, Peter Dedecker, Josef Lazar.
      Genetically encoded fluorescent biosensors convert specific biomolecular events into optically detectable signals. However, imaging biomolecular processes often requires modifying the proteins involved, and many molecular processes are still to be imaged. Here, we present a biosensor design that uses a hitherto overlooked detection principle: directionality of optical properties of fluorescent proteins. The biosensors (termed FLIPs) offer an extremely simple design, high sensitivity, multiplexing capability, ratiometric readout, and other advantages, without requiring modifications to their targets. We demonstrate the sensor performance by real-time imaging activity of G protein-coupled receptors (GPCRs), G proteins, arrestins, and other membrane-associated proteins, as well as by identifying a previously undescribed, pronounced, endocytosis-associated conformational change in a GPCR-β-arrestin complex. In combination with an original tri-scanning linear dichroism confocal microscope, FLIPs allow unparalleled imaging of activity of nonmodified, endogenously expressed G proteins. Thus, FLIPs establish a powerful molecular platform for imaging cell signaling, allowing numerous future developments and insights.
    DOI:  https://doi.org/10.1126/sciadv.adz5662
  9. Blood Adv. 2026 Jan 15. pii: bloodadvances.2025016879. [Epub ahead of print]
    Antileukemic therapies for older adults with AML ineligible for conventional therapy: systematic review & meta-analysis.
    Maria Jose Oliveros, Saifur R Chowdhury, Yetiani Roldan, Sara Ibrahim, Gonzalo Bravo-Soto, Charles E Foucar, Gurleen Bhogal, Barbara Burgos-Mansilla, Mobina Bagherianlemraski, Hamed Movahed, Ruvistay Gutierrez-Arias, Tanin Khorrami Taj, Yaping Chang, Sayed Kaveh Hadeiy, Roberta Demichelis-Gómez, Luca Malcovati, Kah Poh Loh, Uwe Platzbecker, Linda Gilberto, John Treitz, Maria R Baer, Bernard Lawrence Marini, Ryan J Mattison, Mikkael A Sekeres, Romina Brignardello-Petersen.
      Older adults with newly diagnosed acute myeloid leukemia (AML) are often ineligible for conventional "7+3" induction chemotherapy. Despite recent drug approvals, treatment outcomes remain poor in this population. We conducted an updated systematic review to inform the 2025 American Society of Hematology (ASH) AML update guidelines in older adults. This review compared the efficacy and safety of low-dose cytarabine (LDAC), azacitidine (AZA), 5- and 10-day decitabine (DEC), and gemtuzumab ozogamicin, alone or combined with drugs such as venetoclax (VEN), in older adults with AML ineligible for conventional chemotherapy. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) of adults aged ≥55 years with AML, and synthesized evidence on mortality, remission, quality of life (QoL), functional status, and severe toxicity. We applied GRADE to assess the certainty of evidence. We included 47 studies (30 RCTs, 17 NRS). AZA or LDAC combined with VEN probably reduces mortality and improves remission and QoL. AZA plus isocitrate dehydrogenase-1 (IDH1) inhibitors may reduce 1-year mortality and improve remission and survival in patients with IDH1-mutated AML. Compared with DEC alone, combining DEC with other agents showed inconsistent effects with mostly low certainty of conclusions. VEN combinations showed promising effects on mortality and remission but lacked data on QoL and functional status. In older adults with AML ineligible for conventional therapy, evidence suggests that hypomethylating agents (HMAs) or LDAC combined with VEN likely improves survival and remission outcomes. Treatment decisions should consider patient goals and functional status. These findings informed eight recommendations in updated ASH-AML guidelines.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016879
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