bims-medica 2026-03-01 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–03–01
twenty-one papers selected by
Brett Chrest, Wake Forest University

A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.
The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.
Aspartate availability drives differential engagement of the malate-aspartate shuttle.
Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.
Brain-derived ketone bodies can replace glucose to power neural function.
A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice.
Ketogenic diet therapy for high-grade gliomas combined with standard treatment using an angiogenesis inhibitor: An exploratory pilot study on feasibility.
Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
Modeling lipid homeostasis using stable isotope tracing and flux analysis.
Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.
Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.
Matching-Adjusted Indirect Comparison of Olutasidenib and Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Relapsed/Refractory Acute Myeloid Leukemia.
Venetoclax and azacitidine for younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy.
High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.
Receptor-Mitochondria Crosstalk in the Kynurenine Metabolic Pathway: Integrating Metabolomics and Clinical Mass Spectrometry.
Safety profile of FLT3 inhibitors in acute myeloid leukemia: a systematic review and meta-analysis of adverse events.
Rethinking mitochondria as a target for cancer therapy.
The protein carriers of hundreds of lipids have been identified.
Specific SLC25 carriers regulate mitochondrial protein synthesis.

Blood. 2026 Feb 24. pii: blood.2024027853. [Epub ahead of print]

A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.

Ekaterini Himonas, Lucie de Beauchamp, Désirée Zerbst, Eudoxie Desmares-Romain, Daniele Sarnello, Eric R Kalkman, Kevin M Rattigan, Daniel James, Engy Shokry, Mhairi Copland, Emmanuel Griessinger, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, David Sumpton, Aaron D Schimmer, Mark D Minden, Eyal Gottlieb, Emma Shanks, Jean-Emmanuel Sarry, Vignir Helgason.

Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances the effects of standard chemotherapy and overcomes treatment resistance in pre-clinical models of acute myeloid leukaemia (AML). So far, the few clinically available OXPHOS inhibitors have shown adverse effects or limited potency in clinical trials, therefore, identification of safe and effective drugs that can target mitochondrial metabolism in AML is critical. Here, we performed a high-throughput drug-repurposing screen, designed to identify clinically applicable OXPHOS-specific inhibitors through nutrient sensing. We uncover itraconazole, an FDA-approved antifungal compound, as a potent OXPHOS inhibitor in AML cells. Mechanistically, through stable isotope-assisted metabolomics and functional studies, we reveal that CYP51A1, which is part of the cytochrome P450 family and the prime target of azole antifungals, is involved in mitochondrial respiration and ETC complex I activity in AML cells. Critically, we demonstrate that itraconazole and related azole antifungals interfere with tricarboxylic acid cycle activity and inhibit OXPHOS through the inhibition of electron transport chain complex I activity. Over-expression of yeast NADH dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity upon itraconazole treatment. Using patient-derived cells and pre-clinical xenograft models, we demonstrate that itraconazole targets therapy-resistant leukaemic stem cells (LSCs) when used in combination with cytarabine, highlighting the repurposing potential for itraconazole as a clinically safe and effective therapeutic option for AML LSC eradication.

DOI: https://doi.org/10.1182/blood.2024027853
PLoS One. 2026 ;21(2): e0329048

The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.

Hernán A Tirado, Nithya Balasundaram, Jean Jacobs, Fleur Leguay, Lotfi Laaouimir, Nick van Gastel.

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.

DOI: https://doi.org/10.1371/journal.pone.0329048
Free Radic Biol Med. 2026 Feb 19. pii: S0891-5849(26)00147-4. [Epub ahead of print]248 210-221

Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.

Ryan J Mailloux.

Alpha-ketoglutarate dehydrogenase (KGDH; EC 1.2.4.2) catalyzes the fourth step of the tricarboxylic acid (TCA) cycle and links carbohydrate, fatty acid and amino acid metabolism to the aerobic production of ATP. KGDH is classically viewed as indispensable to energy metabolism and strictly located to mitochondria. Therefore, it is generally thought that the loss of its activity has catastrophic consequences for mammalian cells. However, recent advances in molecular biology and redox biology tools coupled with the implementation of new genetically modified mouse lines and cultured cells knocked down for components of KGDH have revealed it is a multifunctional cellular enzyme that localizes to the mitochondria and nucleus where it uses superoxide (O2•-)/hydrogen peroxide (H2O2) and metabolites related to its catalysis (e.g., alpha-ketoglutarate (KG), succinyl-CoA, succinate) to control cell fate decisions. In addition, it has been revealed that over-stimulation of KGDH causes severe oxidative stress through the hyper-production of O2•-/H2O2 and disturbs cell signals and epigenome regulation, which has been linked to cancer cell transformation, metabolic diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), and inflammation. Furthermore, inhibition of KGDH with competitive inhibitors, redox modifications, or shRNAs has shown that the targeted disruption of the enzyme can alleviate these diseases. The aim of this review is to update the literature on KGDH. It is not just a TCA cycle enzyme anymore.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.02.050
Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]

Aspartate availability drives differential engagement of the malate-aspartate shuttle.

Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.

  The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.

Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation

DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
Curr Oncol. 2026 Feb 23. pii: 129. [Epub ahead of print]33(2):

Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.

Sabrina Guo, Christina L Addison.

  Metabolic reprogramming is a defining feature of breast cancer, enabling tumor cells to sustain rapid proliferation, survive under stress, and resist therapy. Key pathways including glycolysis, glutaminolysis, lipid metabolism, and one-carbon metabolism, play central roles in meeting the energetic and biosynthetic demands of malignant cells. Enhanced glycolytic flux supports ATP generation and lactate production, while glutamine metabolism fuels the tricarboxylic acid cycle and provides nitrogen for nucleotide synthesis. Lipid metabolic pathways, particularly fatty acid synthesis, contribute to membrane biogenesis and signaling, and one-carbon metabolism driven by serine and glycine supplies methyl groups for epigenetic regulation and nucleotide production. These metabolic adaptations not only promote tumor growth but also create vulnerabilities that can be exploited therapeutically. Inhibiting these pathways has shown promise in preclinical models; however, challenges such as metabolic plasticity, tumor heterogeneity, and potential toxicity in normal tissues underscore the need for biomarker-driven strategies and rational combination therapies. Herein, we describe current knowledge of the role of these pathways in breast cancer progression, highlighting the role of key enzymes in promoting breast cancer tumor cell growth and in breast cancer prognoses.

Keywords:  TCA cycle; breast cancer; fatty acids; glutaminolysis; glycolysis; metabolism; pentose phosphate pathway; prognosis; serine biosynthesis; tumor growth

DOI:  https://doi.org/10.3390/curroncol33020129
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706813. [Epub ahead of print]

Brain-derived ketone bodies can replace glucose to power neural function.

Hafsa Yaseen, Karissa Cisneros, Rebecca Wright, Nikolaus Bueschke, Joseph M Santin.

The brain is sensitive to disruptions in glucose metabolism, requiring constant delivery to support neural activity. Here, we discovered a vertebrate with the surprising capacity to abandon glucose metabolism and replace it with ketone bodies produced entirely within the brain. In frogs-animals with seemingly typical glucose demands-hibernation shifts brain bioenergetics to allow ketone bodies made within the brain to sustain neural activity without ATP from glucose metabolism. This involves, in part, the upregulation of fatty acid catabolism, ketone body synthesis, and transport from astrocytes to neurons to maintain synaptic transmission. Brain-derived ketone bodies also prevent decrements in activity that otherwise occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise impair neural performance. Overall, these results reveal a capacity for the vertebrate brain to temporarily abandon glucose while maintaining costly functions using locally sourced ketone bodies independent from body energy stores.

DOI: https://doi.org/10.64898/2026.02.19.706813
Nat Commun. 2026 Feb 25. pii: 1656. [Epub ahead of print]17(1):

A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice.

Pattarawan Pattamaprapanont, Roberto C Nava, Rea Grover, Mia Formato, Eileen M Cooney, Ana Paula Pinto, Ana B Alves-Wagner, Anamica Das, Yuntian Guan, Meghana Annambhotla, Saanvi Acharya, Donato A Rivas, Sarah J Lessard.

VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we show that reducing blood glucose with a carbohydrate-restricted, high fat ketogenic diet can restore aerobic exercise adaptation in male mice with hyperglycemia. Hyperglycemic mice received standard high-carbohydrate chow (CHOW), which sustains high blood glucose; or a ketogenic diet (KETO), which normalizes blood glucose levels. After aerobic exercise training, improvements in VO2peak are blunted in CHOW, but restored by KETO. Increased VO2peak in KETO is associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density. Moreover, KETO induces exercise-independent effects on muscle mitochondrial remodeling and substrate selection, significantly increasing fatty acid oxidation and down-regulating glucose metabolism. We identify a ketogenic diet as a potential therapy to improve aerobic exercise adaptation in the growing population with hyperglycemia.

DOI: https://doi.org/10.1038/s41467-026-69349-5
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf264

Ketogenic diet therapy for high-grade gliomas combined with standard treatment using an angiogenesis inhibitor: An exploratory pilot study on feasibility.

Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Michiko Takahashi, Misa Yamanishi, Misaki Kuroda, Satoko Tabuchi, Keisuke Hagihara, Shunsuke Yamanishi, Yusuke Ikeuchi, Yuichi Fujita, Hirohumi Iwahashi, Sayaka Hotta, Michiko Matsunaga, Shoji Sanada, Yoshihiro Muragaki, Masamitsu Nishihara.

   Background: Altered tumor metabolism has renewed interest in ketogenic strategies, despite limited clinical evidence in glioma. Whereas the ketogenic diet (KD) alone elevates intratumoral amino acids, bevacizumab (BEV) co-administration suppresses these metabolites and curtails tumor growth, pointing to a synergistic therapeutic potential.
Methods: We conducted a clinical pilot study to evaluate the combination of KD and standard therapy, combining BEV, in patients with malignant glioma. A standardized modified ketogenic diet (mKD) regimen was implemented: carbohydrate intake was restricted to 10 g/day in the first week, 20 g/day in the following 2 months, and ≤30 g/day thereafter. MCT oil was administered at ≥50 mL/day, and ketone formula supplements were provided as needed. The primary endpoint was to assess safety and feasibility.
Results: 10 patients were enrolled. The duration of mKD ranged from 63 to 1,954 days, with a median of 185 days. All patients showed a rapid increase in serum ketone levels and achieved therapeutically adequate glucose-ketone index values. All participants met the predefined safety criteria, and no severe adverse events were reported. One patient discontinued the diet owing to moderate abdominal pain. The objective response rate was 50%, and notably, one patient remained on mKD for more than 5 years without tumor recurrence. The median progression-free survival from mKD initiation was 9.5 months, and the median overall survival was 31 months.
Conclusions: The combination of mKD and standard therapy with BEV was safe and feasible in patients with malignant glioma. Larger clinical trials are needed to determine its anti-tumor efficacy and clinical benefit.

Keywords:  angiogenesis inhibitor; feasibility; ketogenic diet; malignant glioma; safety

DOI:  https://doi.org/10.1093/noajnl/vdaf264
iScience. 2026 Mar 20. 29(3): 114889

Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.

Huabo Wang, Jie Lu, Colin Henchy, Steven J Mullett, Adam C Richert, Eric S Goetzman, Ahmet Toksoz, Leonardo Hale, Brandon B Wang, Nelli Mnatsakanyan, Edward V Prochownik.

  Cancer cell metabolic re-programming provides the additional energy and anabolic precursors necessary to sustain unregulated proliferation. This is partially mediated by the Warburg effect, which generates ATP while oxidizing glucose to a subset of these anabolites. Concurrently, mitochondrial mass and ATP generation via oxidative phosphorylation decline in most tumors. This raises the question of how increased glycolysis-derived anabolites can be balanced with those supplied by the TCA cycle. Using primary murine liver cancers and their derivative cell lines, we show that this can be explained by the dissociation of mitochondrial Complex V (CV or ATP synthase) into its component and functionally independent Fo and F1 domains. This occurs as a result of marked declines in MT-ATP6, a CV subunit that stabilizes Fo-F1 assembly. Serving as a proton pore, free Fo maintains a normal mitochondrial membrane potential without generating ATP, thus allowing the TCA cycle, electron transport chain, and anaplerotic reactions to function at high levels. Concurrently, free F1 functions in reverse as an ATPase to limit excess ATP accumulation. The uncoupling of TCA-cycle-derived anabolic substrate production from membrane hyperpolarization and ATP overproduction by a smaller population of highly efficient mitochondria allows TCA-cycle-generated anabolic precursors to match those generated via glycolysis.

Keywords:  Biochemistry; Cancer; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.114889
Cell Metab. 2026 Feb 20. pii: S1550-4131(26)00020-3. [Epub ahead of print]

Modeling lipid homeostasis using stable isotope tracing and flux analysis.

Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Christopher W Murray, Yale Huang, Ethan L Ashley, Hector M Galvez, Grace H McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.

  Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.

Keywords:  ELOVL1; LKB1; TP53; ceramide; lipid homeostasis; metabolic flux analysis; non-small cell lung cancer; precision-cut lung slice culture; sphingolipids; very long-chain fatty acids

DOI:  https://doi.org/10.1016/j.cmet.2026.01.020
Biochim Biophys Acta Bioenerg. 2026 Feb 25. pii: S0005-2728(26)00006-X. [Epub ahead of print] 149586

Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.

Victor V Lemeshko.

  Glycerophosphate shuttle, an important crossroad between oxidative phosphorylation system, glycolysis and lipid metabolism, consists of the rate-limiting mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) and the cytosolic dehydrogenase (GPD1). GPD2 level is relatively high in islet beta-cells, spermatozoa and neurons, required abruptly rapid periodic ATP consumption, as well as in rapidly growing normal tissues during neonatal period and many cancers. According to the computational model developed in the present work, the glycerophosphate shuttle should be significantly activated by the outer membrane potential (OMP) generated by the VDAC1,2-hexokinase complexes of mitochondrial outer membrane. This is due to the capture of cytosolic glycerol-3-phosphate2- into the mitochondrial intermembrane space by the positive OMP, thus increasing its local concentration near GPD2. The predicted acceleration is most significant at relatively high Km of GPD2 for glycerol-3-phosphate2- and strongly modulated by the VDAC's voltage-gating properties. In general, OMP generated by the VDAC1,2-hexokinase complexes might play a crucial role in the above-mentioned crossroad, converting it into the "electrical metabolic crossroad". The suggested electrical deviation of glycolysis towards the mitochondrial GPD2, as a tool for the metabolic shift to an accelerated aerobic glycolysis without an inhibition of mitochondrial respiration, highlights this metabolic switching as one of the possible options of the Warburg effect.

Keywords:  Glycerophosphate shuttle; Glycolysis; Hexokinase; Mitochondria; Outer membrane potential; VDAC

DOI:  https://doi.org/10.1016/j.bbabio.2026.149586
Blood. 2026 Feb 26. pii: blood.2025031202. [Epub ahead of print]

Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.

Ekaterina N Parfenova, Nikolina Vrdoljak, Drake Mosca, Juan J Aristizabal-Henao, Michael A Kiebish, Mark D Minden, Paul A Spagnuolo.

Altered lipid metabolism enables growth of acute myeloid leukemia (AML) cells. While mitochondrial lipid oxidation is well characterized, the contribution of peroxisomal fatty acid oxidation (pFAO) is unclear. In this study, we demonstrate that AML cells upregulate the peroxisomal very-long-chain fatty acid (VLCFA) transporter ABCD1 and increase endogenous levels of pFAO relative to healthy hematopoietic cells. Genetic silencing or pharmacological inhibition of ABCD1, with eicosenol, impairs pFAO causing accumulation of VLCFAs and selective AML cell death in vitro and in vivo. Loss of ABCD1 disrupts peroxisomal fatty acid import and lipid homeostasis in AML, while normal progenitors remain viable by upregulating glycolysis. In murine models, ABCD1 inhibition with eicosenol reduces leukemia burden and prolongs survival without toxicity. These findings identify ABCD1 as a regulator of pFAO and a novel anti-AML therapeutic target.

DOI: https://doi.org/10.1182/blood.2025031202
Adv Ther. 2026 Feb 28.

Matching-Adjusted Indirect Comparison of Olutasidenib and Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

Justin M Watts, Eunice S Wang, Brian A Jonas, Florence R Wilson, Julie E Park, Shannon Cope, Aaron Sheppard, Amber Thomassen, Stéphane de Botton, Jorge E Cortes.

   INTRODUCTION: Olutasidenib and ivosidenib are isocitrate dehydrogenase 1 (IDH1) inhibitors approved for relapsed/refractory (R/R) IDH1 mutant (IDH1m) acute myeloid leukemia (AML).
METHODS: A matching-adjusted indirect comparison estimated relative treatment effects using registrational Phase I/II data for olutasidenib (Study 2102-HEM-101; individual patient data) and ivosidenib (Study AG120-C-001; study-level data) since a head-to-head trial is unlikely. Weights were estimated using a logistic propensity score model adjusted for pre-defined covariates identified from a literature review, validated by clinical experts. Eight covariates were determined to be the most important prognostic factors/effect modifiers for the target population as reported in the Food and Drug Administration labels: number of prior systemic therapies, age, prior hematopoietic stem cell transplantation, AML type, relapse type, cytogenetic risk, Eastern Cooperative Oncology Group performance status, and IDH1 mutation.
RESULTS: Olutasidenib versus ivosidenib adjusted rates of complete remission (CR; odds ratio [OR] 1.12, 95% confidence interval [CI] 0.61-2.08), CR plus CR with partial hematologic recovery (CR + CRh; OR 0.83, 95% CI 0.46-1.50), and median CR duration (difference in medians 11.18 months, 95% CI - 4.30 to 22.72) were not significantly different. Median CR + CRh duration was significantly longer for olutasidenib (difference in medians 9.84 months, 95% CI 3.24-22.28), accompanied by a numerical non-significant trend in overall survival that should be considered exploratory (hazard ratio 0.75, 95% CI 0.53-1.07).
CONCLUSION: While not confirmatory, these findings may be clinically relevant in the context of this difficult-to-treat R/R IDH1m AML population.

Keywords:  Isocitrate dehydrogenase 1-mutated; Ivosidenib; Matching-adjusted indirect comparison; Olutasidenib; Relapsed/refractory acute myeloid leukemia

DOI:  https://doi.org/10.1007/s12325-026-03522-6
Haematologica. 2026 Feb 26.

Venetoclax and azacitidine for younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy.

Justin Watts, Ellen Madarang, Diana Abbott, Payton Hart, Connor Sohalski, Alessia Zoso, Jessie Dell-Martin, Ayele Belachew, Maria L Amaya, Andrew Kent, Christine McMahon, Marc Schwartz, Mikkael A Sekeres, Clayton Smith, Terrence Bradley, Justin Taylor, Namrata Chandhok, Sangeetha Venugopal, Craig Jordan, Mary Berg, Mary Haag, Nicholas Willard, Dara Aisner, Jeffrey Schowinsky, Zenggang Pan, Jinjing Zhang, Jonathan A Gutman, Daniel A Pollyea.

Venetoclax (ven)+azacitidine (aza) is the standard of care for newly-diagnosed acute myeloid leukemia (AML) patients who are not candidates for intensive chemotherapy (IC). Because prognostic factors for ven/aza and IC differ, an AML patient fit for IC may derive more benefit from ven/aza. We therefore designed a trial for younger, newly-diagnosed AML patients with non-favorable risk disease to receive ven/aza regardless of "fitness" for IC. We aimed to understand toxicity and efficacy in this population, and retrospectively compared outcomes to matched IC patients. Newly-diagnosed non-favorable risk patients ≤60 were enrolled and received ven, dose escalated to 600mg/dailyx28 days, with aza 75mg/m2x7 days on a 28-day cycle. Subjects were encouraged to move expeditiously to allogeneic stem cell transplant (ASCT) in first remission. Thirty-six subjects enrolled. Median age was 49 (22-59). Grade ≥3 neutropenia(42%), anemia(33%), thrombocytopenia(53%) and febrile neutropenia(36%) were common. The overall response rate (ORR) was 25/36 (69%) with 19 (53%) complete remissions; 68% of responders achieved MRD-negativity. Most subjects (53%) bridged to ASCT, and the majority of non-responders were successfully salvaged with IC. The median progressionfree- survival (PFS) and overall survival (OS) have not been reached (median follow-up 2.9 years). Compared to IC matched controls, the ORR, ASCT rate and PFS were significantly improved (69% vs 44% [p=0.0495], 53% vs 28% [p-0.0290] and not reached vs 60.8 months [p=0.007]). Hospital days, transfusions and infectious complications were significantly reduced for ven/aza subjects. Ven/aza is feasible for newly-diagnosed, younger, non-favorable risk AML patients, and appears at least as effective as IC.

DOI: https://doi.org/10.3324/haematol.2025.300374
Am J Physiol Cell Physiol. 2026 Feb 21.

High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.

Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.

  High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.

Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00545.2025
Front Oncol. 2025 ;15 1606239

A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.

Dhabya Majid, Zhe Wang, Amanda M Schalk, Bin Yuan, Qi Zhang Tatarata, Jessica L Root, Araceli Isabella Garza, Mhd Yousuf Yassouf, Basant T Gamal, Sammy Feri-Borgogno, Annie Hoai Nguyen, Marina Konopleva, Evelien Peeters, Ying Su, Patrick K Reville, Farhad Ravandi-Kashani, Arnon Lavie, Hussein A Abbas.

   Introduction: Acute myeloid leukemia (AML) remains a malignancy with poor prognosis andfrequent resistance to standard therapies, underscoring the urgent need for novel treatmentstrategies. In this preclinical study, we evaluated the anti-leukemic efficacy of EBD-300, a novelmammalian-derived asparaginase lacking glutaminase activity, in combination with Venetoclax(VEN).
Results: EBD-300 monotherapy exhibited significant activity in AML cell lines harboringchromosome 7/7q deletions, which are likely dependent on extracellular asparagine due to thepresence of only a single copy of the asparagine synthetase (ASNS) gene - the enzymeresponsible for endogenous asparagine synthesis. The combination of EBD-300 with VENdecreased the IC50 values of some VEN-resistant AML cell lines and reduced the colony-formingcapacity of primary AML patient samples. In patient-derived xenograft (PDX) mouse models,EBD-300, alone or in combination with VEN, significantly reduced leukemic burden in theperipheral blood, bone marrow, and spleen, and improved overall survival in one model.
Discussion: Although survival benefits were observed in some, but not all, models, suggestingpotential model-specific effects, these findings collectively support a potential therapeutic roleEBD-300 in combination with VEN in AML. While weight loss was observed, EBD-300 mayrepresent a potentially safer alternative to conventional bacterial asparaginases by mitigatingthe adverse effects typically associated with the glutaminase coactivity of the bacterialasparaginases, an observation that requires further investigation.

Keywords:  AML; AML with deletion 7; acute myeliod leukemia; asparaginase; combination treatment; leukemia; venetoclax

DOI:  https://doi.org/10.3389/fonc.2025.1606239
Antioxidants (Basel). 2026 Feb 19. pii: 261. [Epub ahead of print]15(2):

Receptor-Mitochondria Crosstalk in the Kynurenine Metabolic Pathway: Integrating Metabolomics and Clinical Mass Spectrometry.

László Juhász, Zsolt Galla, Masaru Tanaka, László Vécsei.

  Mitochondria govern energy transfer, redox balance, and cell fate. Tryptophan catabolism generates kynurenines (KYNs) that can tune mitochondrial function, with growing evidence that G protein-coupled receptor 35 (GPR35), aryl hydrocarbon receptor (AhR), and N-methyl-D-aspartate receptors (NMDA receptors) link extracellular cues to adenosine 5 prime triphosphate (ATP) maintenance, calcium (Ca2+) handling, mitophagy, and inflammasome control. In parallel, quinolinic acid (QA)-driven de novo nicotinamide adenine dinucleotide (NAD+) synthesis connects KYN flux to tricarboxylic acid (TCA) cycle activity and sirtuin programs across tissues. Key gaps remain: receptor pharmacology is rarely integrated with NAD+ economics and respiration, and clinical workflows still lack single-run assays that quantify both kynurenine and TCA nodes. We therefore integrate receptor proximal signaling, QA-driven NAD+ supply, and unified liquid chromatography-mass spectrometry (LC-MS) measurement into one translational framework spanning kynurenic acid (KYNA), KYN, 3-hydroxykynurenine (3-HK), and QA, using mitochondrial endpoints as the common readout. We synthesize evidence for mitochondrial GPR35 signaling that preserves ATP, AhR programs that tune oxidative defenses and mitophagy, and NMDA receptor antagonism that limits excitotoxic stress. These mechanisms are linked to QA-dependent NAD+ biogenesis and alpha ketoglutarate control points, then aligned with chromatography and ionization choices suited to routine LC-MS workflows. This receptor to organelle framework couples KYN flux to respiratory control and provides a practical roadmap for standardized single-run LC-MS panels. It can strengthen target validation in ischemia, neurodegeneration, psychiatry, and oncology while improving biomarker qualification through harmonized analytics and decision-grade readouts.

Keywords:  G protein-coupled receptors; N-methyl-D-aspartate (NMDA); aryl hydrocarbon receptor (AhR); kynurenic acid (KYNA); liquid chromatography–mass spectrometry (LC-MS); metabolomics; mitochondria; mitophagy; nicotinamide adenine dinucleotide (NAD+); receptors; tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.3390/antiox15020261
Clin Exp Med. 2026 Feb 23.

Safety profile of FLT3 inhibitors in acute myeloid leukemia: a systematic review and meta-analysis of adverse events.

Mario Gaio, Alessia Zinzi, Valerio Liguori, Cecilia Cagnotta, Mario Frasca, Ludovica Vittoria Laino, Francesco Rossi, Annalisa Capuano.

  Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Approximately 30% of patients present alterations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene, which are associated with poor prognosis. FLT3 inhibitors - midostaurin (first-generation), gilteritinib and quizartinib (second-generation) - have been developed to block FLT3 activation. Given the need of optimizing treatment in FLT3-mutated AML, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the safety profiles of FLT3 inhibitors. Following the PRISMA statement, we searched Embase, MEDLINE and Cochrane Library. The Cochrane Risk of Bias Tool for RCTs was used for quality assessment. Of 2132 references, seven RCTs, involving 2409 adult patients, met inclusion criteria: quizartinib and midostaurin in two trials each and gilteritinib in three. The most frequently reported adverse events (AEs) were classified under the System Organ Class (SOC) Blood and lymphatic system disorders (N = 5474, 58.4% of them related to FLT3 inhibitors). The most frequently observed non-hematological AEs were gastrointestinal disorders, pyrexia, elevated ALT/AST and headache. FLT3 inhibitors are not associated with a significant increase in the risk of AEs compared to standard treatments. No meaningful differences in AE risk were observed among the three drugs. The only exception was an higher risk of ALT increased with gilteritinib (RR = 2.40, 95% CI: 1.16-4.95). Future studies should stratify safety outcomes by demographic and clinical characteristics and incorporate long-term follow-up for a more comprehensive safety assessment in clinical practice.

Keywords:  Acute myeloid leukemia; FLT3 inhibitors; Gilteritinib; Midostaurin; Quizartinib; Safety

DOI:  https://doi.org/10.1007/s10238-026-02093-8
Trends Mol Med. 2026 Feb 26. pii: S1471-4914(25)00289-8. [Epub ahead of print]

Rethinking mitochondria as a target for cancer therapy.

Lucia Minarrieta, Julie St-Pierre.

  In recent years, numerous studies have highlighted the crucial role of mitochondrial metabolism in cancer progression. This sparked interest in its potential as a target for cancer therapy and prompted the clinical evaluation of multiple drugs targeting mitochondrial metabolism. Regrettably, most have showed limited efficacy and safety, raising concerns about the viability of mitochondrial inhibitors in cancer treatment. However, emerging evidence suggests that shifting the focus away from mitochondrial bioenergetics and targeting other aspects of mitochondrial biology, may have a meaningful impact on cancer progression with milder side effects. In this review, we discuss emerging actionable targets and strategies to tailor the administration of inhibitors of mitochondrial pathways for cancer therapy.

Keywords:  cancer; metabolism; metastasis; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.molmed.2025.12.002
Nature. 2026 Feb 25.

The protein carriers of hundreds of lipids have been identified.



Keywords:  Cell biology; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-00570-4
Sci Adv. 2026 Feb 27. 12(9): eaeb0049

Specific SLC25 carriers regulate mitochondrial protein synthesis.

Danielle L Rudler, Laetitia A Hughes, Martin S King, Jessica Baker, Richard G Lee, Andrianto P Gandadireja, Anisha Sunil, Samuel V Fagan, Blake Payne, Nicola Gray, Tim McCubbin, Edmund R S Kunji, Oliver Rackham, Aleksandra Filipovska.

A genome-wide knockout screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange adenosine triphosphate-magnesium (ATP-Mg) and phosphate, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multiomic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilized by choline, and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodeling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function and show that impaired transport of branched-chain amino acids, methylated basic amino acids, ATP-Mg, and choline affects mitochondrial translation.

DOI: https://doi.org/10.1126/sciadv.aeb0049