bims-medica 2026-05-31 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–05–31
twenty-two papers selected by
Brett Chrest, Wake Forest University

AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.
Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.
Lactylation landscape of mitochondrial proteins in myocardial infarction.
Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
Effects of Low-Carbohydrate and Ketogenic Diets on Anaerobic Performance in Competitive Athletes: A Systematic Review and Meta-Analysis.
CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.
Obesity suppresses neutrophil-dependent itaconate signaling promoting ferroptosis in acute pancreatitis.
Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.
In vivo quantification of mitochondrial O2 affinity in human skeletal muscle using 1H-magnetic resonance spectroscopy of deoxy-myoglobin.
Real-time cell viability monitoring for high-throughput drug screening using tumor xenograft-derived cells.
Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
A price check on the ketogenic diet for adults with epilepsy in Australia.
Leveraging Dietary Interventions to Benefit Patients with Hematologic Malignancies and Clonal Hematopoiesis.
Exploring the Bone Marrow Microenvironment as a Therapeutic Barrier and Targetable Source of Crosstalk in Acute Myeloid Leukemia.
Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.
The Influence of Diet on Cancer Progression and Treatment.
Leukemia stem cells in acute myeloid leukemia: biology, therapeutic resistance, and barriers to durable remission.
Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML.
Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.

Mol Cancer. 2026 May 27.

AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.

Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.

BACKGROUND: mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking.
METHODS: We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types.
RESULTS: Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53-mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care.
CONCLUSIONS: As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.

DOI: https://doi.org/10.1186/s12943-026-02689-4
Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00791-4. [Epub ahead of print]253 221-237

Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.

Ehsaneh Khodadadi, Bingwei Lu.

  Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In addition to driving ATP synthesis through oxidative phosphorylation (OxPhos), MCI is a dynamic redox regulator that couples bidirectional catalysis with redox signaling. MCI conducts electron transfer in both the forward and reverse directions. While forward electron transport (FET) is essential for OxPhos and ATP synthesis, reverse electron transport (RET), driven by high membrane potential and ubiquinol pool, transfers electrons from ubiquinol to NAD+ and produces excessive ROS. MCI-derived ROS and NAD+/NADH changes act as physiologically regulated signals mediating hypoxia sensing, immune activation, stem-cell metabolism, but they can also contribute to pathology when dysregulated as in ischemia-reperfusion, cancer, neurodegeneration, and aging. Recent cryo-EM structures, time-resolved studies, and multiscale molecular dynamics (MD) simulations have provided near-atomic views of MCI architecture and operational mechanics. Here we review these developments from a redox-centered perspective. By positioning MCI as a dynamic redox regulator within a spatially organized mitochondrial network, we aim to provide a unifying framework for understanding how directional electron transfer, proton translocation, and redox signaling are intertwined in mitochondrial biology.

Keywords:  Mitochondrial Complex I; Proton-coupled electron transfer; Reactive oxygen species (ROS); Redox signaling; Reverse electron transport (RET)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.311
Transl Cancer Res. 2026 Apr 30. 15(4): 345

Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia.

Juan Luiz Coelho-Silva, Diego Antonio Pereira-Martins, João Agostinho Machado-Neto.



Keywords:  Acute myeloid leukemia (AML); B-cell lymphoma 2-mediated apoptosis (BCL2-mediated apoptosis); mitochondrial dysfunction; nicotinamide adenine dinucleotide metabolism (NAD+ metabolism); nicotinamide phosphoribosyltransferase inhibition (NAMPT inhibition)

DOI:  https://doi.org/10.21037/tcr-2026-1-0292
Redox Biol. 2026 May 18. pii: S2213-2317(26)00224-7. [Epub ahead of print]94 104226

Lactylation landscape of mitochondrial proteins in myocardial infarction.

Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.

  Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently discovered lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we mapped the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocyte-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.

Keywords:  AZD3965; Lactate; Lactylation; MCT1; Mitochondria; Myocardial infarction

DOI:  https://doi.org/10.1016/j.redox.2026.104226
Nat Cancer. 2026 May 25.

Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.

Alan Y L Wong, Jacob W Myers, Gyan Prakash, Alice Ma, Jeannette R Brook, Boryana Petrova, Baran Bulut, Ralph White, Catherine Merz, Maeve de Souza, Adam G Maynard, Peng Wang, Amy Yu, Nancy K Pohl, Michal Weitman, Lewis B Silverman, Kimberly Stegmaier, L Stirling Churchman, Peter D Cole, Donita C Brady, Naama Kanarek.

The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.

DOI: https://doi.org/10.1038/s43018-026-01177-4
Clin Cancer Res. 2026 May 26.

Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.

Evan C Chen, Yiwen Liu, Hayden L Bell, Jeremy Ryan, Jason Wu, Emma-Jayne Minihane, Marlise R Luskin, Eric S Winer, Rahul Vedula, Virginia Volpe, Maximillian Stahl, Daniel Roberts, Ilene Galinsky, Mary Gerard, Matthew Hersch, Jessica Lee, Donna Neuberg, Richard M Stone, Daniel J DeAngelo, Anthony Letai, Andrew A Lane, Jacqueline S Garcia.

BACKGROUND: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies.
PATIENTS AND METHODS: We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts.
RESULTS: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects.
CONCLUSION: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4905
Nutrients. 2026 May 16. pii: 1589. [Epub ahead of print]18(10):

Effects of Low-Carbohydrate and Ketogenic Diets on Anaerobic Performance in Competitive Athletes: A Systematic Review and Meta-Analysis.

Mateusz Gawelczyk, Jakub Chycki, Adam Maszczyk, Adam Zając.

   BACKGROUND/OBJECTIVES: Low-carbohydrate (LCD) and ketogenic diets (KD) are increasingly adopted by athletes due to their ability to enhance fat oxidation and induce metabolic adaptations. While their effects on aerobic power and capacity have been widely investigated, their influence on anaerobic performance remains unclear. Given the strong dependence of high-intensity exercise on glycolytic metabolism and muscle glycogen availability, carbohydrate restriction may have significant implications for short-duration maximal efforts and repeated high-intensity exercise. Therefore, this systematic review and meta-analysis aimed to evaluate the effects of LCD and KD on anaerobic performance outcomes in trained athletes.
METHODS: A comprehensive search of five electronic databases (PubMed, SCOPUS, Web of Science, SPORTDiscus, and Cochrane Central Register of Controlled Trials) identified 13 unique studies (yielding 15 study-level entries across three anaerobic performance domains) meeting comprehensive inclusion criteria. Individual study sample sizes ranged from n = 5 to n = 65 participants, reflecting substantial inter-study variability that should be considered when interpreting pooled estimates. Outcomes included peak and mean power output, repeated sprint performance, blood lactate responses, and markers of substrate utilization. Study quality was assessed using the Newcastle-Ottawa Scale, and meta-analyses were performed using random-effects models where appropriate.
RESULTS: Overall, the effects of carbohydrate-restricted diets on anaerobic performance were domain-specific. Some studies reported maintained or slightly improved peak power during single maximal efforts, while others showed no effect. Impairments were more consistently observed in repeated high-intensity exercise. Repeated sprint performance was impaired in several studies, likely reflecting reduced muscle glycogen availability and limited glycolytic ATP production. Carbohydrate restriction consistently increased fat oxidation and was associated with lower blood lactate concentrations during high-intensity exercise. Random-effects meta-analyses yielded domain-specific pooled effect sizes: maintained-to-slightly-improved anaerobic power output (Cohen's d = +0.29; 95% CI: -0.08 to +0.66), modestly impaired repeated sprint ability (d = -0.33; 95% CI: -0.80 to +0.14), and a large, consistent reduction in blood lactate concentration (d = -0.89; 95% CI: -1.20 to -0.58). Given substantial between-study heterogeneity in intervention durations (2 days to 12 weeks), dietary composition, athlete populations, and outcome measures (1RM, Wingate, CMJ within the power domain; varied protocols within the RSA and lactate domains), these pooled estimates should be interpreted as exploratory rather than confirmatory.
CONCLUSIONS: LCD and KD appear to have domain-specific effects on anaerobic performance in trained athletes. Although single, short-duration efforts may be preserved in some contexts, repeated, high-intensity performance appears to be more susceptible to impairment. These findings highlight the importance of aligning dietary strategies with the metabolic demands of training and competition.

Keywords:  anaerobic performance; fat oxidation; ketogenic diet; low-carbohydrate diet; sports nutrition; sprint performance; trained athletes

DOI:  https://doi.org/10.3390/nu18101589
Cell Death Dis. 2026 May 28.

CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.

Kuanbing Chen, Shi Zong, Kefeng Li, Li Yu.

Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (CPT1A) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, CPT1A is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of CPT1A reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting CPT1A markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.

DOI: https://doi.org/10.1038/s41419-026-08868-x
Redox Biol. 2026 May 21. pii: S2213-2317(26)00228-4. [Epub ahead of print]94 104230

Obesity suppresses neutrophil-dependent itaconate signaling promoting ferroptosis in acute pancreatitis.

Néstor Jiménez-Cañete, Alicia Aliena-Valero, Caroline A Bressan, Salvador Pérez, Isabel Torres-Cuevas, Laura Benkenstein, Sandra Pinto, Antonio Cuadrado, Juan Sastre, Sergio Rius-Pérez.

Obesity is a well-established risk factor for increased severity and mortality in acute pancreatitis. However, the mechanisms by which obesity alters pancreatic immune regulation and favors the progression of acute pancreatitis are not elucidated yet. Here, we identify a neutrophil-driven immune-metabolic pathway that controls ferroptosis during pancreatic inflammation. We show that infiltrating myeloid cells represent the principal source of the immunometabolite itaconate during acute pancreatitis. Through paracrine transfer via the SLC13A3 transporter, myeloid-derived itaconate protects pancreatic acinar cells from ferroptosis by sustaining NRF2-dependent antioxidant responses. Obesity disrupts this protective axis by suppressing ACOD1 expression in infiltrating neutrophils. Proteomic profiling of pancreatic neutrophils from obese mice confirmed reduced ACOD1 abundance and decreased expression of enzymes linked to the tricarboxylic acid cycle and pyruvate metabolism. This metabolic reprogramming limits itaconate production and weakens NRF2-driven redox defenses, leading to downregulation of the xCT-GPX4 ferroptosis-protective pathway and increased lipid peroxidation in the pancreas of obese mice with pancreatitis. Pharmacological restoration of itaconate signaling with the cell-permeable derivative 4-octyl itaconate reactivates NRF2 signaling, the xCT-GPX4 antioxidant axis, and the trans-sulfuration pathway, mitigating pancreatic injury. Together, these findings identify neutrophil-derived itaconate as a key modulator of ferroptosis susceptibility and reveal immune cell metabolism as a critical determinant of obesity-associated severity in acute pancreatitis.

DOI: https://doi.org/10.1016/j.redox.2026.104230
bioRxiv. 2026 May 11. pii: 2026.05.06.723011. [Epub ahead of print]

Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.

Shih Ming Huang, Hannah R Foster, Eun Young Lee, Jeong Hun Jo, Xinhang Dong, Byoung-Kyu Cho, Young Ah Goo, Jing W Hughes, Matthew J Merrins.

Primary cilia are antenna-like sensory and signaling organelles present on most mammalian cells, including glucose-sensing pancreatic β-cells. Here, we show that the local energetic demands of primary cilia require the ATP-producing enzyme pyruvate kinase, with loss of PKm1, but not PKm2, impairing ciliary glycolytic flux. While the entire glycolytic machinery localizes to cilia, our data indicate that mitochondria are a critical source of phosphoenolpyruvate (PEP), the high-energy glycolytic intermediate that drives the pyruvate kinase reaction. Abolishing PCK2, the mitochondrial enzyme that generates PEP, prevents cilia from sensing not only glucose but also the amino acids glutamine and leucine. Finally, by mislocalizing glycolysis, we demonstrate that primary cilia can utilize ATP generated within the cell body when glucose is limiting. These findings indicate that primary cilia, while possessing the capacity for local ATP generation, leverage a ciliary-mitochondrial signaling axis to meet their bioenergetic needs.

DOI: https://doi.org/10.64898/2026.05.06.723011
J Physiol. 2026 May 24.

In vivo quantification of mitochondrial O2 affinity in human skeletal muscle using 1H-magnetic resonance spectroscopy of deoxy-myoglobin.

Muhammet Enes Erol, Alexs A Matias, Corinna F Serviente, Stephen T Decker, Rajakumar Nagarajan, Saadallah Ramadan, Yann Le Fur, Song-Young Park, Gwenael Layec.

  Mitochondrial oxygen (O2) affinity is a fundamental determinant of oxidative phosphorylation capacity, which has yet to be directly measured in human skeletal muscle in vivo. To determine the apparent mitochondrial O2 affinity (i.e. P50) of the skeletal muscle, we used proton-magnetic resonance spectroscopy (1H-MRS) of deoxymyoglobin (dMb) during a circulatory occlusion of the lower limb to simultaneously quantify intracellular partial pressure of O2 (i PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) and resting tissue-specific O2 consumption ( V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) in the gastrocnemius muscle of sedentary young adults. Under these resting conditions, the V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ -i PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ relationship conformed to a Michaelis-Menten kinetics model (goodness of fit: r2 = 0.84 ± 0.13). The estimated Vss, reflecting basal metabolic rate, reached 0.20 ± 0.06 mM min-1, and the apparent mitochondrial P50 was 0.50 ± 0.38 mmHg. Vss and P50 were positively correlated (r = 0.85, P = 0.0009). This strong correlation remained after log transformation (r = 0.82, P = 0.0020). These results, obtained in human muscles in vivo, demonstrate that mitochondrial respiration exhibits a very high O2 affinity (P50 ≈ 0.5 mmHg). In addition, it quantitatively identifies the range across which oxidative phosphorylation in the skeletal muscle is O2-independent (resting i PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ under physiological conditions) or becomes O2-sensitive (severe exercise and hypoxia). Moreover, the finding that muscle respiratory flux was associated with the apparent mitochondrial O2 affinity suggests additional regulatory mechanisms within the respiratory chain to fine-tune oxidative phosphorylation to muscle ATP demand even at rest. This study provides a robust quantitative framework for interpreting in vivo respiratory control in both health and disease. KEY POINTS: Mitochondrial oxygen affinity (P50) is central to oxidative phosphorylation, yet has not been directly quantified in human skeletal muscle in vivo. Using deoxymyoglobin 1H-MRS during 8 min of lower-limb ischaemia, we simultaneously measure intracellular partial pressure of O2 (i PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) and resting tissue-specific O2 consumption ( V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) in the resting gastrocnemius of healthy young adults. The V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ - PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ relationship followed Michaelis-Menten kinetics, yielding a Vss of 0.20 mM min-1 and an apparent mitochondrial P50 of 0.50 mmHg, indicating very high O2 affinity. Resting apparent mitochondrial P50 was far below previously reported i PO2${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ (∼34 mmHg), indicating a wide O2-independent range and identifying conditions (severe hypoxia, high-intensity exercise) in which oxidative phosphorylation becomes O2-sensitive. Vss and P50 were positively correlated (r = 0.85), suggesting in vivo coupling between respiratory flux and oxygen affinity and providing a potential quantitative framework for interpreting mitochondrial respiratory control in health and disease.

Keywords:  O2 cascade; deoxymyoglobin 1H‐magnetic resonance spectroscopy; intracellular oxygen partial pressure; mitochondrial oxygen affinity; skeletal muscle oxidative phosphorylation

DOI:  https://doi.org/10.1113/JP290548
Cell Rep Methods. 2026 May 27. pii: S2667-2375(26)00164-5. [Epub ahead of print] 101464

Real-time cell viability monitoring for high-throughput drug screening using tumor xenograft-derived cells.

Elham Esmaeilishirazifard, Daniel Guerrero-Romero, Allan J W Lui, Abigail Shea, Long V Nguyen, Maurizio Callari, Riccardo Masina, Kevin Tu, Richard Baird, Paul Edwards, Wendy Greenwood, Steve Fuller, Claire Crafter, Mandy Lawson, Alejandra Bruna, Oscar M Rueda, Carlos Caldas.

  Patient-derived tumor xenografts (PDTXs) recapitulate the molecular and phenotypic heterogeneity of human cancers, making them valuable pre-clinical models for cancer drug development. However, high-throughput drug screening (HTDS) using ex vivo short-term cultures of PDTX-derived tumor cells (PDTCs) is hindered by endpoint viability assays that provide only static measures of drug response. Here, we establish an optimized a screening platform by validating the RealTime-Glo (RTG) bioluminescent assay for dynamic, real-time measurements of PDTC viability. We further introduce an analytical metric to quantify drug responses independent of cell growth rate. Using this approach, we screened 67 compounds across 43 breast cancer PDTCs and revealed model-specific pharmacodynamic heterogeneity. Our PDTC-based HTDS pipeline improves assay robustness and offers an enhanced platform for leveraging patient-derived xenograft models in precision medicine.

Keywords:  CP: cancer biology; PDTCs; PDTX-derived tumor cells; PDTXs; breast cancer; drug response kinetics; dynamic viability monitoring; ex vivo drug sensitivity; high-throughput drug screening; isotonic regression modeling; patient-derived tumor xenografts; pharmacodynamic profiling; real-time viability monitoring

DOI:  https://doi.org/10.1016/j.crmeth.2026.101464
EMBO J. 2026 May 27.

Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.

Tanveer Ahmed, Hui Zhang, Ghulam M Mushraf, Yongzhang Pan, Zeyu Zhang, Zhenzhu Sun, Mengran Yin, Xueting Xu, Xinyu Wu, Yin Gao, Yan Li, Peizhi Li, Liang Ding, Qiang Zhang, Runxia Lin, Khair Ullah, Yinghua Huang, Bushra Mirza, Yifeng Huang, Abdul Sammad, Xiangqian Kong, Dajiang Qin, Miguel A Esteban, Lulu Wang, Baoming Qin.

The electron transport chain (ETC) is essential for NAD+ regeneration and proliferation. While many cell types tolerate ETC inhibition when pyruvate or aspartate is supplied, pluripotent stem cells (PSCs) enter a reversible paused state even at abundant pyruvate levels. Here, we show that ETC inhibition triggers severe NADH reductive stress in mouse embryonic stem cells (mESCs), driven mainly by threonine dehydrogenase (TDH). TDH-derived NADH establishes a metabolic environment that disfavors cells with compromised mitochondrial function, maintains inhibition of pyruvate dehydrogenase (PDH), and is associated with increased genomic and epigenetic stability at the cellular population level. ETC inhibition similarly induces pausing in early mouse embryos and in human pluripotent stem cells (hPSCs). In hPSCs, combined inhibition of the one-carbon metabolism enzymes serine hydroxymethyltransferase (SHMT1/2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) effectively reduced reductive stress and rescued the paused phenotype. Together, these findings support a model in which limited mitochondrial redox adaptability represents a conserved metabolic feature of pluripotent stem cells and in which NADH reductive stress is associated with genomic and epigenetic stability.

DOI: https://doi.org/10.1038/s44318-026-00784-2
Epilepsia Open. 2026 May 25.

A price check on the ketogenic diet for adults with epilepsy in Australia.

Lillian King, Jessica Maccarrone, Ashwinpreet Kaur, Susanna Chen, Patrick Kwan, Terence J O'Brien, Neha Kaul.

   OBJECTIVE: The ketogenic diet is an established and effective treatment for drug-resistant epilepsy and is an emerging therapy for other conditions. Affordability of therapeutic ketogenic diets for epilepsy has not been well studied. This study aimed to compare weekly cost of ketogenic diets with national dietary guidelines and a typical Australian diet.
METHOD: Seven-day meal plans were created for a reference male and female, aged 31-50 years, for five diets: classical ketogenic, modified ketogenic, specialty modified ketogenic, national dietary guidelines, and a typical Australian diet. Prices were obtained from three supermarkets.
RESULTS: For females, the classical ketogenic diet ($70.07AUD) and typical Australian diet ($75.91AUD) were cheaper than the national dietary guidelines ($99.23AUD). For males, all ketogenic diet types and the national dietary guidelines ($94.81-119.60AUD) were more expensive than the typical Australian diet ($82.98). Following the dietary guidelines, modified or specialty modified ketogenic diets increased food costs by 9%-31% for females and 26%-44% for males compared to current spending on a typical Australian diet.
SIGNIFICANCE: Our study demonstrates that, for males aged 31-50 years, ketogenic diet therapy for epilepsy is more expensive than the typical Australian diet. Financial assistance may be considered to reduce barriers to dietary therapy for epilepsy.
PLAIN LANGUAGE SUMMARY: A specialized ketogenic diet is an effective treatment for managing epilepsy when medication has been ineffective at controlling seizures. This study shows that some ketogenic diets for epilepsy cost more than a typical Australian diet. The higher costs may stop people from starting or staying on this helpful treatment. Providing financial support to help pay for these diets could make them easier to follow and allow more people to access this treatment. This could help more people manage their seizures and lower the long-term costs of epilepsy for the healthcare system and society.

Keywords:  cost analysis; dietary therapy; epilepsy; ketogenic diet

DOI:  https://doi.org/10.1002/epi4.70285
Nutrients. 2026 May 14. pii: 1562. [Epub ahead of print]18(10):

Leveraging Dietary Interventions to Benefit Patients with Hematologic Malignancies and Clonal Hematopoiesis.

Camille Brzechffa, Angela G Fleischman.

  Diet is a modifiable factor that influences multiple pathways relevant to hematologic malignancy, including systemic inflammation, immune cell activity, gut microbiota composition, and cancer cell metabolism. Translation of preclinical findings into clinical practice for hematologic malignancies remains nascent, although momentum is building to evaluate dietary interventions as a component of supportive and disease-modifying care. This review examines the mechanistic rationale for dietary interventions across the spectrum of clonal hematologic disorders and synthesizes current clinical evidence. Anti-inflammatory dietary patterns, particularly the Mediterranean diet, have demonstrated reductions in pro-inflammatory cytokines and may attenuate the inflammatory milieu that fuels clonal expansion. Obesity, which elevates the risk of developing hematologic malignancies and worsens clinical outcomes in diseases such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia, may be addressed through calorie-restricted, low-fat, or plant-based dietary strategies. Gut microbiota dysbiosis induced by chemotherapy represents another target, with high-fiber and plant-based diets showing promise in restoring microbial diversity and potentially enhancing treatment efficacy. Early-phase clinical trials in multiple myeloma, acute lymphoblastic leukemia, and myeloproliferative neoplasms have established feasibility and yielded preliminary signals warranting larger confirmatory studies. Larger, rigorously designed trials are needed to establish dietary interventions as legitimate therapeutic tools in the management of hematologic malignancies.

Keywords:  CHIP; Mediterranean diet; acute leukemia; clonal hematopoiesis; dietary intervention; gut microbiome; inflammation; multiple myeloma; myeloproliferative neoplasm; obesity; plant-based diet

DOI:  https://doi.org/10.3390/nu18101562
Blood Lymphat Cancer. 2026 ;16 511758

Exploring the Bone Marrow Microenvironment as a Therapeutic Barrier and Targetable Source of Crosstalk in Acute Myeloid Leukemia.

Aleksandra Kolosova, Imogen Anna Mould, Chris Pepper, Simon Mitchell, Andrea G S Pepper, Eleni E Ladikou, Fabio A Simoes.

  Acute myeloid leukemia (AML) is an aggressive and genetically heterogeneous hematological malignancy characterized by the accumulation of immature myeloid blasts that disrupt healthy hematopoiesis. Despite advances in molecular profiling and targeted therapies, overcoming drug resistance and relapse remains a significant clinical challenge, resulting in poor long-term outcomes. Crucially, disease persistence is sustained not merely by intrinsic genetic lesions but by a highly adaptive bone marrow microenvironment (BMME) that functions as a therapeutic barrier. While the healthy niche tightly regulates hematopoietic stem cell maintenance, leukemic blasts co-opt stromal, vascular, and immune components to establish a sanctuary that fuels proliferation and shields the disease from cytotoxic stress. However, dissecting these reciprocal dependency mechanisms uncovers critical vulnerabilities, presenting a vital opportunity to develop novel targeted therapies. In this review, we discuss the architecture of the healthy BMME and its pathological AML-driven remodeling. We describe the role of specific signaling axes that govern AML-BMME crosstalk and evaluate targeted therapeutic strategies designed to uncouple these protective interactions. Finally, we highlight that current preclinical models lack the complexity of the BMME stromal components and its spatial organization, a limitation that continues to hinder clinical translation and delay the development of effective combination therapies.

Keywords:  acute myeloid leukemia; bone marrow microenvironment; targeted therapy; therapeutic resistance

DOI:  https://doi.org/10.2147/BLCTT.S511758
bioRxiv. 2026 May 17. pii: 2026.05.15.725497. [Epub ahead of print]

Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.

Yaw Akosah, Ioannis Azoidis, Dane Jensen, Paolo Bernardi, Evgeny Pavlov.

Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and cristae dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the sub-organellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K + ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K + influx leads to increase of mitochondrial matrix volume while stimulation of K + efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.

DOI: https://doi.org/10.64898/2026.05.15.725497
Cancer Lett. 2026 May 26. pii: S0304-3835(26)00379-4. [Epub ahead of print] 218616

SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.

Xiaoyan He, Zhengwei Zhao, Teng Wei, Lisi Zheng, Jincui Yang, Xinrong He, Yicai Cheng, Xiaoyi Zhan, Zejuan Li, Kelin Wu, Stephanie Roessler, Yunting Jian, Chuli Fu, Guang-Rong Yan, Junyao Xu, Qiangnu Zhang.

Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses peroxisome proliferator-activated receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.

DOI: https://doi.org/10.1016/j.canlet.2026.218616
Annu Rev Nutr. 2026 May 26.

The Influence of Diet on Cancer Progression and Treatment.

Anna M Barbeau, John W R Kincaid, Alissandra L Hillis, Edrees H Rashan, Yichi Zhang, Gillian E Oaks, Matthew G Vander Heiden.

Growing evidence suggests that dietary interventions can influence cancer progression and patient outcomes. Here, we discuss mechanistic links between diet and cancer biology including those related to systemic hormone signaling, modulation of nutrient availability within the tumor microenvironment, and interactions with the immune system and microbiome, while highlighting their interconnectedness. Further, we review preclinical and clinical data evaluating specific diets, including their use with cancer therapies. Given the interest in diet as an adjunct to cancer care, it is essential to establish evidence-based dietary strategies for optimizing patient outcomes and quality of life.

DOI: https://doi.org/10.1146/annurev-nutr-062122-021518
J Biomed Res (Middlet). 2026 ;7(1): 41-45

Leukemia stem cells in acute myeloid leukemia: biology, therapeutic resistance, and barriers to durable remission.

Giovannino Silvestri.

DOI: https://doi.org/10.46439/biomedres.7.083
Blood Adv. 2026 May 27. pii: bloodadvances.2026019841. [Epub ahead of print]

Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML.

Nicholas J Short, Hagop M Kantarjian, Naval G Daver, Roberta S Azevedo, Omer Karrar, Courtney D DiNardo, Tapan M Kadia, Musa Yilmaz, Manuel M Maroun, Maria Catherine Rita Hachem, Gautam Borthakur, Ghayas C Issa, Elizabeth J Shpall, Uday R Popat, Xuelin Huang, Wei Qiao, Lewis Fady Nasr, Walid Macaron, Regina Abramova, Guillermo Garcia-Manero, Marina Konopleva, Farhad Ravandi.

In patients with FLT3-mutated AML who receive frontline azacitidine plus venetoclax, relapses are commonly driven by expansion of the FLT3-mutated clone, providing rationale for "triplet" FLT3 inhibitor-based lower-intensity regimens. Here we report long-term outcomes of a phase II study of azacitidine, venetoclax and gilteritinib in adults with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. Thirty patients were treated; the median age was 71 years, and 22 (73%) had a FLT3-ITD mutation. The complete remission (CR)/CR with incomplete hematologic recovery rate was 96%, and 14 patients (47%) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. With a median follow-up of 41.5 months, 11 patients (37%) relapsed; in 67% of evaluable relapses, the FLT3 mutation was not detectable. The median RFS and OS were 23.4 and 29.7 months, respectively, and the 3-year RFS and OS rates were 43% and 46%, respectively. Among patients with FLT3-ITD-mutated AML, the median RFS and OS were 17.0 and 21.8 months, respectively, and the 3-year RFS and OS rates were 32% and 36%, respectively. The presence of a baseline RAS pathway mutation was associated with worse outcomes. Survival rates were similar regardless of HSCT in first remission. Among patients who received at least one consolidation cycle, 68% had a reduction in the dose or duration of at least one of the study drugs. The triplet regimen of azacitidine, venetoclax and gilteritinib is associated with durable remissions and encouraging long-term survival. Randomized studies comparing this regimen to standard of care approaches are warranted. This trial is registered at www.clinicaltrials.gov #NCT04140487.

DOI: https://doi.org/10.1182/bloodadvances.2026019841
Nat Chem Biol. 2026 May 27.

Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.

Zhiqiang Hu, Wei Lv, Ting Wen, Junyi Sun, Guimei Ji, Shuo Ru, Xue Sun, Zheng Wang, He Ren, Yudi Zhang, Pengkun Chen, Linlin Zhou, Shiqi Wu, Xiaoqian Jia, Shanshuo Liu, Zheng Zhu, Jiawei Xu, Tong Liu, Yuxiong Feng, Gaopeng Li, Yuan Ding, Yuhao Wang, Yang Luo, Chang Liu, Zhimin Lu, Zhigang Ren, Sheng-Zhong Duan, Daqian Xu.

Understanding of the metabolic determinants influencing immunotherapy responsiveness remains limited. Here we performed a multiomics analysis of tumor biopsies from patients with hepatocellular carcinoma (HCC) treated with immune checkpoint blockade (ICB) and revealed that heightened expression of OXCT1, a rate-limiting enzyme in ketone body metabolism, was negatively correlated with ICB efficacy, whereas its metabolic substrate, β-hydroxybutyrate (BHB), displayed an opposite effect. Mechanistically, glucose deprivation in HCC cells promotes AMPK-mediated OXCT1 S113 phosphorylation, which exposes the nuclear localization sequence of OXCT1 to trigger its nuclear translocation. Nucleus-translocated OXCT1 associates with IRF1 to locally consume BHB and suppress histone H3K9 BHB at the major histocompatibility complex class I (MHC-I) and chemokine gene loci, leading to repressed transcription of these immune genes. Targeting the AMPK-OXCT1-IRF1 axis sensitizes tumor cells to ICB upon ketogenic diet. These findings reveal a mechanism by which a non-canonical function of nuclear OXCT1 coordinates the interplay between ketone body metabolic reprogramming and immunotherapy responsiveness.

DOI: https://doi.org/10.1038/s41589-026-02229-7