bims-medica 2026-05-03 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–05–03
twenty papers selected by
Brett Chrest, Wake Forest University

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.
TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
Stable Isotopes for the Study of Energy Nutrient Metabolic Pathways in Relation to Health and Disease.
Reprogramming lipid metabolism in pediatric cancers.
Ketogenic diet-induced changes in adult lipid metabolism: a comprehensive systematic review and meta-regression of randomized controlled trials.
Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.
Nicotinamide Reverses the Warburg Effect in CHO Cell Culture.
Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation.
Acute myeloid leukemia after myeloproliferative neoplasms: Real-world outcomes in the new treatment era in the United States.
Mild ketosis, metabolic syndrome, and genetic-lifestyle interactions in the UK Biobank.
Conversion of a bifurcating ETF to a canonical ETF by site-directed mutagenesis.
Inhibition of Cyclophilin D Rescues Cardiac Function and Bioenergetic Defects Caused by Neonatal Hypoxia.
Cristae: bridging bioenergetic hubs and compartmental barriers in mitochondrial homeostasis.
Trends in Long-Term Survival Among Patients With De Novo Metastatic Cancer.
Nintedanib is a potent FLT3 inhibitor with activity against FLT3-ITD and overcomes the gatekeeper F691L resistance mutation in acute myeloid leukemia.
Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.
Low oxygen environment alters transcripts related to energy metabolism without altering the pluripotency core of bovine embryonic stem cells.
Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.

Nat Metab. 2026 Apr 29.

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

Stable isotope-tracing assays track few metabolites, yet cells use many nutrients to sustain nitrogen metabolism. Here we create a platform for tracing 30 nitrogen isotope-labelled metabolites in parallel to enable a system-level understanding of cellular nitrogen metabolism. This platform reveals that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine. This link between cell state and pyrimidine synthesis pathway preference persists in murine and human tissues. Mechanistically, we find that S1900 phosphorylation of CAD, the first enzyme of the de novo pathway, is induced by uridine deprivation in differentiated cells and constitutively enriched in primitive cells. Mimicking CAD S1900 phosphorylation in differentiated cells constitutively activates de novo pyrimidine synthesis, while blocking this modification impairs the cellular response to uridine starvation. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

DOI: https://doi.org/10.1038/s42255-026-01520-0
Cell Death Dis. 2026 Apr 28.

DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.

Ferial Khalife, Elodie Muzotte, Fatima Naji, Walid Mahfouf, Julien Izotte, Benoît Pinson, Stéphane Claverol, Nivea Amoedo, Hussein Fayyad-Kazan, Lea Dousset, Rodrigue Rossignol, Hamid-Reza Rezvani.

Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in the initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. We also showed that pharmacological inhibition of this enzyme suppresses ultraviolet (UV)-induced tumor formation. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. We investigated the biological consequences of pharmacological and genetic DHODH inhibition in cSCC using xenograft models derived from two human cell lines, A431 and SCC13, implanted in immunodeficient NSG mice. DHODH activity was suppressed pharmacologically with leflunomide (LFN) and the potent DHODH inhibitor PTC299, or genetically via lentiviral shRNA-mediated DHODH silencing (shDHODH). Proteomic and metabolomic analyses were integrated with histopathological, immunohistochemical, and immunoblotting evaluations to delineate the downstream effects of DHODH blockade. Comprehensive proteomic and metabolomic profiling revealed that DHODH inhibition induces a coordinated adaptive program involving keratinization, differentiation, redox homeostasis, and metabolic stress responses. Histological and immunostaining analyses demonstrated marked reductions in Ki67-positive proliferating cells and a corresponding increase in pan-cytokeratin (PanCK) and keratin 10 (Krt10) expression, indicative of enhanced epithelial differentiation. These changes were most pronounced in PTC299-treated and shDHODH xenografts, whereas LFN displayed minimal or no efficacy in SCC13 tumors. DHODH inhibition drives tumor differentiation and suppresses proliferation in cSCC, highlighting metabolic dependency as a potential therapeutic vulnerability. PTC299 exhibited superior antitumor activity and differentiation-inducing capacity compared with LFN. These findings position DHODH as a promising target for bioenergetic vulnerability-based cancer therapy in advanced or treatment-resistant cSCC.

DOI: https://doi.org/10.1038/s41419-026-08815-w
Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]

TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.

  Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.04.004
Metabolites. 2026 Mar 31. pii: 231. [Epub ahead of print]16(4):

Stable Isotopes for the Study of Energy Nutrient Metabolic Pathways in Relation to Health and Disease.

Dalila Azzout-Marniche, Daniel Tomé.

  Background: Stable isotope-based analytical methods have brought about a significant transformation in the study of energy nutrient metabolism, enabling precise in vivo measurement of metabolic fluxes at systemic, tissue, and organ-specific levels in both healthy and diseased states. The regulation of these metabolic fluxes is governed by dynamic interactions between proteins, lipids, carbohydrates, and their precursors-such as glucose, fatty acids, and amino acids-as well as final metabolic products. Discussion: Advanced analytical technologies, including nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), which can offer enhanced precision, have been developed for investigating nutrient metabolism and fluxes in humans, providing precise information on metabolic pathways. These techniques have primarily utilized stable isotopes, such as 2H, 13C, 15N, and 18O, which have largely replaced radioactive isotopes and are now central to metabolic research. These isotopes have been used to label glucose, fatty acids, or amino acids-the main biomolecular precursors-enabling detailed investigation at systemic, tissue, and organ-specific levels of carbohydrate, lipid, and protein metabolism, and revealing pathway alterations associated with diseases conditions, such as diabetes, non-alcoholic fatty liver disease, cardiovascular disorders, and cancer. The use of deuterium oxide (D2O) has allowed for long-term metabolic studies, providing a cost-effective and less invasive means to monitor metabolic changes over days to months. Total daily energy expenditure can be measured in free living conditions by the doubly stable isotopes 2H- and 18O-labeled water method. Stable isotope tracing, combined with advanced imaging and modeling, has also been instrumental in assessing body composition, energy expenditure, and nutrient bioavailability. Collectively, these methods have expanded our understanding of human physiology and disease, supporting the development of novel diagnostic tools, the identification of new biomarkers, and the tailoring of nutritional and therapeutic interventions. Conclusions: This review aimed to provide an overview of the applications of stable isotopes for the study of energy nutrient metabolic pathways. The ongoing integration of stable isotope approaches with artificial intelligence, omics technologies, and miniaturized detection techniques could promise to further refine our understanding of human metabolism and drive advances in personalized medicine.

Keywords:  amino acid; fatty acid; glucose; nutrient metabolism; protein; stable isotopes

DOI:  https://doi.org/10.3390/metabo16040231
Oncogenesis. 2026 Apr 30.

Reprogramming lipid metabolism in pediatric cancers.

Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher.

Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.

DOI: https://doi.org/10.1038/s41389-026-00617-1
BMC Cardiovasc Disord. 2026 Apr 30.

Ketogenic diet-induced changes in adult lipid metabolism: a comprehensive systematic review and meta-regression of randomized controlled trials.

Juanjuan Zhao, Chia Wei, Fao Gong, Zongran Pang, Huanhu Zhao.



Keywords:  Diet; Ketogenic diet; Lipids; Meta-analysis; Systematic review

DOI:  https://doi.org/10.1186/s12872-026-05799-5
Cancer Discov. 2026 Apr 29.

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.

Christian Felipe Ruiz, Xiangyu Ge, Rylee McDonnell, Sherry S Agabiti, Daniel C McQuaid, Andy Tang, Meera Kharwa, Jennifer Goodell, Rocio Del M Saavedra-Pena, Allison Wing, Guangtao Li, Natasha Pinto Medici, Marie E Robert, Rohan R Varshney, Michael C Rudolph, Fred S Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew S Rodeheffer, Mandar Deepak Muzumdar.

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0734
Biotechnol Bioeng. 2026 Apr 29.

Nicotinamide Reverses the Warburg Effect in CHO Cell Culture.

James Morrissey, Ayca Cankorur-Cetinkaya, Luigi Grassi, Annie J Harwood-Stamper, Jonathan Welsh, Ryte Poskute, Kasia Kozakowska-McDonnell, Cleo Kontoravdi.

The Warburg effect, the preferential conversion of glucose-derived pyruvat to lactate despite available oxygen, is a key feature of Chinese hamster ovary (CHO) cell culture. Lactate accumulation in recombinant protein-producing cell culture is an inefficient usage of glucose, as well as being deleterious to cells. Lactate accumulation lowers culture pH, requiring base addition to maintain bioreactor pH setpoint, which subsequently leads to hyperosmolarity, adversely impacting cell growth, productivity and product quality. A key driver for the Warburg effect, and hence lactate accumulation, is the need to regenerate NAD+ consumed during glycolysis. Since oxidative phosphorylation has limited capacity to recycle NADH back to NAD+ at high glycolytic fluxes, cells rely on lactate dehydrogenase (LDH) to convert pyruvat to lactate, simultaneously regenerating NAD+ and sustaining glycolysis. Thus, providing the cells' capacity to generate more NAD+ would decrease the reliance on the Warburg effect. In this study, feeding the NAD+ precursor nicotinamide (NAM) leads to reversal of the Warburg effect, inducing the "lactate shift" 3 days earlier in cell culture and reducing peak lactate concentration by 40%. Transcriptomic analysis further confirms this metabolic shift, with an upregulation of key mitochondrial electron transport chain genes. NAM supplementation increased Fc galactosylation without affecting fucosylation, sialylation, or high-mannose species. These results identify NAD+/NADH balance as a key regulator of the Warburg effect and demonstrate NAM supplementation as a simple, cost-effective strategy to mitigate lactate accumulation and improve metabolic efficiency in CHO cell cultures.

DOI: https://doi.org/10.1002/bit.70224
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718012. [Epub ahead of print]

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.

Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.

Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

DOI: https://doi.org/10.64898/2026.04.14.718012
bioRxiv. 2026 Apr 15. pii: 2026.04.13.718201. [Epub ahead of print]

Loss of Propionyl-CoA Carboxylase Reprograms Hepatic Metabolism by Suppressing Mitochondrial Pyruvate Carboxylation and Fatty Acid Oxidation.

Fang Lu, Chorlada Paiboonrungruang, Wentao He, Zhaohui Xiong, Pingchuan Tang, Takhar Kasumov, Xiaoxin Chen, Guo-Fang Zhang.

Propionic acidemia (PA) is an inborn error of metabolism caused by propionyl-CoA carboxylase (PCC) deficiency due to mutations in either PCCA or PCCB . Without proper management, the disease is associated with high mortality. Even with dietary restriction, patients often develop complications later in life, and the underlying pathological mechanisms remain poorly understood. The liver is the primary organ responsible for propionyl-CoA metabolism, yet the metabolic alterations induced by PCC deficiency in the liver have not been systematically investigated. In this study, we used a hepatocyte model of PA- PCCA null - HepG2 cells-to comprehensively examine metabolic alterations using stable isotope-based metabolic flux analysis. The PCCA knockout recapitulated key metabolic features of PA in HepG2 cells. Furthermore, PCCA deficiency reduced mitochondrial fatty acid oxidation while increasing glucose oxidation through pyruvate dehydrogenase. In contrast, pyruvate anaplerosis via pyruvate carboxylase was markedly reduced in PCCA knockout cells. This reduction in anaplerotic flux impaired the capacity for gluconeogenesis and lipid synthesis, consistent with observations from in vivo studies in Pcca⁻/⁻ (A138T) mice. Additionally, branched-chain keto acid catabolism was reduced in PCCA knockout HepG2 cells. Threonine showed minimal metabolic contribution in this model, further supporting the role of propionate as a major source of propionyl-CoA production. Collectively, these findings highlight the metabolic vulnerabilities associated with PCC deficiency and underscore the increased risk of prolonged fasting in patients with PA, particularly those with severe disease.

DOI: https://doi.org/10.64898/2026.04.13.718201
Cancer. 2026 May 01. 132(9): e70415

Acute myeloid leukemia after myeloproliferative neoplasms: Real-world outcomes in the new treatment era in the United States.

Jan Philipp Bewersdorf, Rong Wang, Lourdes Mendez, Alain Mina, Luis E Aguirre, Maximilian Stahl, Amer M Zeidan, Xiaomei Ma, Nikolai A Podoltsev.

   BACKGROUND: Progression to acute myeloid leukemia (AML) is a rare complication of myeloproliferative neoplasms (MPNs) with limited treatment options and median overall survival (OS) of 3-6 months. The treatment of AML has been revolutionized in recent years with the introduction of novel targeted therapies including the BCL2 inhibitor venetoclax (VEN). However, evidence regarding outcomes in patients with post-MPN AML remains limited.
METHODS: To evaluate the impact of novel therapies on the outcomes of patients with post-MPN AML, the authors conducted a retrospective analysis of 392 patients who were diagnosed with post-MPN AML during 2014-2024 in the United States and were included in the Flatiron Health Research Database.
RESULTS: Although the proportion of patients treated with lower-intensity therapies (LIT) including VEN in combination with hypomethylating agents increased over time, OS was very similar among patients diagnosed before and after VEN approval (median OS, 7.1 [95% confidence interval (CI), 5.7-9.5] months vs. 7.6 [95% CI, 5.8-10.1] months; p = .39). Only 15% of post-MPN AML patients underwent an allogeneic hematopoietic cell transplant (allo-HCT). Those who received allo-HCT experienced better OS than patients who did not receive allo-HCT (median OS, 20.5 [95% CI, 15.4-36.2] months vs. 5.8 [95% CI, 5.0-6.8] months; p < .01). Although patients treated with intensive chemotherapy (IC) had longer OS than those treated with LIT (hazard ratio, 1.95; 95% CI, 1.12-3.41; p = .02), patients receiving IC and LIT as a bridge to allo-HCT had comparable OS (p = .37).
CONCLUSIONS: This study highlights allo-HCT as the only potentially curative option with both IC and LIT serving as effective bridging therapies.

Keywords:  acute myeloid leukemia, (AML); myeloproliferative neoplasms, (MPN); novel therapies; transplant; venetoclax

DOI:  https://doi.org/10.1002/cncr.70415
Br J Nutr. 2026 Apr 27. 1-41

Mild ketosis, metabolic syndrome, and genetic-lifestyle interactions in the UK Biobank.

Sunmin Park, Jae Won Choi.

  The relationship between mild ketosis and metabolic syndrome (MetS) remains unclear. We aimed to investigate the association between serum ketone levels and MetS, and to examine how genetic and lifestyle factors influence this relationship. We conducted a cross-sectional observational study using data from the UK Biobank, comprising 269,178 participants. Participants were categorized into low and high serum ketone groups based on β-hydroxybutyrate levels (cutoff: 0.12 mM). Dietary patterns were assessed using validated questionnaires, and a polygenic risk score (PRS) was generated to examine genetic influences on ketone metabolism. Individuals with higher ketone levels showed significantly lower MetS prevalence, with reduced body mass index, waist circumference, triglycerides, and glucose levels, alongside higher HDL-cholesterol. These individuals also exhibited distinct dietary patterns, characterized by lower carbohydrate and higher fat intake, as well as increased physical activity. The PRS was inversely associated with MetS risk, particularly for abdominal obesity, triglyceride, and HDL-cholesterol components. Notably, PRS modified the relationship between plant-based diet and ketone levels, with stronger positive associations observed in individuals with higher PRS. However, a high carbohydrate diet showed weaker associations with PRS. In conclusion, genetic predisposition influenced ketone metabolism and its protective association with MetS risk. The interaction between genetic predisposition and lifestyle factors has crucial clinical implications for developing personalized dietary and lifestyle interventions. This research provides evidence for individualized approaches to optimize metabolic health through targeted ketone metabolism modulation, which could inform precision medicine strategies for MetS prevention and management.

Keywords:  ketone bodies; metabolic syndrome; physical activity; plant-based diet; polygenic variants; β-hydroxybutyrate

DOI:  https://doi.org/10.1017/S0007114526107260
Arch Biochem Biophys. 2026 Apr 24. pii: S0003-9861(26)00104-9. [Epub ahead of print]781 110833

Conversion of a bifurcating ETF to a canonical ETF by site-directed mutagenesis.

Derek Nguyen, Sol Yoon, Wayne Vigil, Dimitri Niks, Russ Hille.

  In an effort to turn a bifurcating ETF (from Megasphaera elsdenii) into a canonical non-bifurcating ETF (from, e.g., Methylophilus methylotrophus), mutagenesis studies were performed to knock out the bf (bifurcating) FAD in Megasphaera elsdenii EtfAB. In order to determine the amino acid residues to mutate, the bf FAD binding site of Acidaminococcus fermentans (homolog to Megasphaera eldenii) was overlaid with the AMP binding site of Methylophilus methylotrophus. Two Megasphaera eldenii EtfAB variants were constructed, one with a single mutation (T132Y), and one with three (G130Q, T132Y, I234 M, also called 3X). These variants did not possess the bf FAD or reconstitute AMP in its place and could no longer be reduced by the median potential donor NADH. The oxidized spectra of the variants were very similar to the spectral contribution of the et (electron-transferring) FAD from the literature, indicating that there was no great difference in the immediate environment of the remaining et FAD. Both variants accumulated the same anionic semiquinone in the course of reductive titration by dithionite as did the wild-type EtfAB, but the variants exhibited an unusual, quite sharp absorption band at ∼730 nm that accumulated and disappeared over the course of titration. Addition of sulfite to the buffer removed this feature, which simplified the observed spectra while otherwise preserving the properties of the variants. In comparing the electron transfer of wild-type EtfAB and the variants, both the forward and reverse directions of electron transfer with bcd (Megasphaera eldenii ETF physiological partner) and the reduction by TMADH (Methylophilus methylotrophus physiological partner) were significantly slowed but still showed evidence of transfer. This work shows how drastically the activity of the et FAD is affected when the bf FAD is removed; however, it is not sufficient to convert a bifurcating ETF to a canonical ETF.

Keywords:  Electron bifurcation; Electron-transferring flavoprotein; Flavin

DOI:  https://doi.org/10.1016/j.abb.2026.110833
JACC Basic Transl Sci. 2026 Apr 24. pii: S2452-302X(26)00062-8. [Epub ahead of print]11(5): 101544

Inhibition of Cyclophilin D Rescues Cardiac Function and Bioenergetic Defects Caused by Neonatal Hypoxia.

Jonathan R Burris, Gisela Beutner, Min Yee, Bartholomew V Simon, Michael F Swartz, Kathryn B Boudreau, Ethan D Cohen, Chaitanya A Kulkarni, Prottoy Hasan, Hongyue Wang, Karen L de Mesy Bentley, György Hajnóczky, George M Alfieris, Eric M Small, Paul S Brookes, Michael A O'Reilly, George A Porter.

  Increased oxygen levels at birth regulate myocyte bioenergetic and structural maturation controlled by mitochondrial cyclophilin D (CypD). We evaluated mechanisms of neonatal hypoxic cardiac dysfunction by exposing neonatal mice to 12% oxygen and studied cardiac bioenergetics, myocyte maturation, and function. Hypoxia decreased the activity/assembly of electron transport chain complex I, uncoupled oxidative phosphorylation, increased proliferation, decreased differentiation, increased ventricular mass, and decreased cardiac function. CypD inhibition rescued most hypoxia-mediated effects and increased cardiac function. In conclusion, neonatal hypoxia alters cardiac bioenergetics, myocyte maturation, and cardiac function through CypD-dependent pathways, providing potential therapeutic targets for neonatal cardiac dysfunction.

Keywords:  NIM811; cardiac development; cardiomyocyte maturation; cyclosporin A; mitochondria

DOI:  https://doi.org/10.1016/j.jacbts.2026.101544
Cell Death Dis. 2026 Apr 25.

Cristae: bridging bioenergetic hubs and compartmental barriers in mitochondrial homeostasis.

Jin Rao, Qian-Qian Wan, Lei Chen, Rong-Bing Tang, Daniya Killedar, Franklin Tay, Li-Na Niu.

Mitochondrial cristae are intricately folded structures of the inner mitochondrial membrane that play essential roles in cellular energy production, metabolic regulation, and compartmentalization. Far from being passive folds, cristae are dynamic, functional entities central to mitochondrial bioenergetics. Their architecture maximizes membrane surface area and spatially organizes protein complexes to enhance oxidative phosphorylation and adenosine triphosphate (ATP) synthesis. The compartmentalized structure of cristae also establishes functional barriers that help maintain localized proton gradients, optimize metabolic reactions, and contribute to mitochondrial stability. These dual roles in energy transformation and spatial segregation underscore the importance of the cristae in supporting cellular homeostasis. The structural design and lipid composition of cristae with enrichment in cardiolipin also reflect their bacterial ancestry, revealing an evolutionary continuity from prokaryotic bioenergetic systems to eukaryotic organelles. Moreover, dynamic remodeling of cristae in response to stress, nutrient availability, and developmental cues highlights their adaptability in regulating mitochondrial performance and signaling pathways. Disruption of cristae architecture is increasingly implicated in neurodegenerative, cardiovascular, and metabolic diseases due to impaired ATP synthesis and compromised mitochondrial integrity. This review examines emerging insights into the organization, composition, and regulatory mechanisms of the cristae, emphasizing their role as both bioenergetic engines and protective compartments. Understanding the complex interplay between cristae structure and mitochondrial function may illuminate novel strategies for restoring mitochondrial health and targeting diseases linked to mitochondrial dysfunction. Cristae represent an evolutionary innovation that bridges structure and function, enabling the mitochondria to meet the multifaceted demands of the eukaryotic cell.

DOI: https://doi.org/10.1038/s41419-026-08779-x
JCO Oncol Pract. 2026 Apr 30. OP2501154

Trends in Long-Term Survival Among Patients With De Novo Metastatic Cancer.

Saad Badat, Braden Lau, Fang Wang, Ming Wang, Daniel M Trifiletti, Luke Rothermel, Richard Hoehn, Melina Hsu, Daniel E Spratt, Nicholas G Zaorsky.

PURPOSE: Although outcomes for nonmetastatic cancers have improved since the 1970s, it remains uncertain whether long-term survival has improved among patients presenting with de novo metastatic disease, defined as cancer presenting with distant metastases at the time of initial diagnosis. This study evaluated changes in 5-year survival among patients with de novo metastatic cancer diagnosed in 1976 versus 2015, with a minimum 5-year follow-up through 1981 and 2020, respectively.
METHODS: Population-based data were obtained from the SEER database. Patients diagnosed with de novo metastatic cancer in 1976 (n = 11,864) and 2015 (n = 26,324) were included. Five-year overall survival (OS) was compared between cohorts, and multivariable logistic regression identified demographic and clinical factors associated with survival.
RESULTS: The 5-year OS increased significantly from 10.6% in 1976-1981 to 23.6% in 2015-2020 (P < .001). Survival gains were largest in breast cancer (12.6%-34.2%; P < .001), ovarian cancer (14.4%-32.5%; P < .001), colorectal cancer (3.7%-15.0%; P < .001), and hematologic malignancies (24.3%-53.9%; P < .001). Minimal improvement occurred in pancreatic cancer (0.25%-1.6%; P = .007) and small cell lung cancer (0.8%-3.1%; P = .008). Multivariable analysis demonstrated that older age, male sex, and Black race were associated with lower odds of 5-year survival (all P < .01).
CONCLUSION: Over the past four decades, long-term survival among patients with de novo metastatic cancer has more than doubled; however, progress remains uneven across cancer types. Gains appear concentrated in malignancies with substantial therapeutic advances, whereas others show persistently poor outcomes. Continued efforts are needed to address disparities and improve survival in resistant cancer types.

DOI: https://doi.org/10.1200/OP-25-01154
Eur J Pharmacol. 2026 Apr 24. pii: S0014-2999(26)00377-8. [Epub ahead of print]1024 178895

Nintedanib is a potent FLT3 inhibitor with activity against FLT3-ITD and overcomes the gatekeeper F691L resistance mutation in acute myeloid leukemia.

Cuiying Gu, Jiajun He, Jiaqi Fan, Caixia Wang, Wei Zhou, Yanli Xu, Tingfen Deng, Shunqing Wang, Peihong Wang.

  Acute myeloid leukemia (AML) is a molecularly heterogeneous malignancy in which FMS-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (FLT3-ITD), occur in approximately 30% of cases and are associated with poor prognosis and high relapse risk. While FLT3 inhibitors have improved clinical outcomes, acquired resistance, often mediated by secondary tyrosine kinase domain (TKD) mutations or other mechanisms, remains a major therapeutic challenge. Nintedanib is an oral multi-kinase inhibitor approved for the treatment of fibrotic lung diseases; however, its potential activity against FLT3-ITD-positive AML has not been explored. Here, we identified nintedanib as a putative FLT3 inhibitor by analyzing drug-sensitivity data from the BeatAML database. Direct target engagement was validated by computational docking, cellular thermal shift assay (CETSA), and in vitro kinase inhibition assays. In FLT3-ITD-mutant human cell lines (MV4-11, MOLM13), primary AML blasts, and engineered Ba/F3 cells expressing FLT3-ITD with or without secondary TKD mutations, nintedanib suppressed FLT3 autophosphorylation and downstream STAT5, ERK, and AKT signaling, leading to cell cycle arrest and apoptosis. Notably, nintedanib retained efficacy against common resistance mutations, including the gatekeeper F691L mutation, both in vitro and in vivo. In a Ba/F3 FLT3-ITD-F691L mouse model, nintedanib demonstrated superior anti-leukemic efficacy compared with gilteritinib and quizartinib. Furthermore, nintedanib potently inhibited primary AML blasts harboring FLT3-ITD while normal bone marrow remained intact. These findings identify nintedanib as a promising FLT3 inhibitor and support its further therapeutic investigation in FLT3-ITD-positive AML.

Keywords:  AML; Drug resistance; FLT3 inhibitor; FLT3-ITD-F691L; Nintedanib

DOI:  https://doi.org/10.1016/j.ejphar.2026.178895
Nat Neurosci. 2026 Apr 30.

Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.

Sami Sauma, Stephanie Stransky, Ipek Selcen, Simone Sidoli, Rinat Abzalimov, Ye He, Patrizia Casaccia.

How it is determined whether postnatal oligodendrocyte progenitor cells (OPCs) will survive, proliferate or differentiate remains unclear. Here we suggest that temporal and brain regional fluctuations of glucose, concomitant with changes in vascularization, modulate OPC population dynamics. We found that regions with high glucose levels exhibited greater OPC proliferation and histone acetylation than regions with low glucose and that this was mediated by the enzyme ATP-citrate lyase (ACLY), which converts glucose-derived citrate to acetyl-CoA. Mice with Acly deletion in OPCs showed a transient hypomyelination phenotype resulting from decreased OPC numbers, whereas their differentiation into oligodendrocytes (OLs) proceeded due to compensatory upregulation of enzymes responsible for extranuclear generation of acetyl-CoA from alternative metabolic substrates. Therefore, OPCs rely on ACLY-dependent nuclear acetyl-CoA from glucose-derived citrate, to regulate proliferation, whereas OLs rely on extranuclear acetyl-CoA from other sources for myelin formation. This suggests a metabolic regulation of OL lineage cell population dynamics.

DOI: https://doi.org/10.1038/s41593-026-02263-7
Biol Open. 2026 Apr 28. pii: bio.062352. [Epub ahead of print]

Low oxygen environment alters transcripts related to energy metabolism without altering the pluripotency core of bovine embryonic stem cells.

R Botigelli, R Braz Arcanjo, C Guiltinan, A J Morton, J M Smith, A C Denicol.

  Stem cell pluripotency is shaped by culture microenvironment. Growth factors, cytokines, and oxygen tension are key regulators of self-renewal and pluripotency state. Here we evaluated the adaptation of bovine embryonic stem cells (bESC) derived on mouse embryonic fibroblasts (MEF) to feeder-free conditions and the effects of low oxygen (5% O2) on their molecular profile. Primed bESC established on MEF and 21% O2 (high oxygen) were adapted to 5% O2 (low oxygen) and to feeder-free conditions in vitronectin to generate four culture conditions: high and low O2 tension in MEF and feeder-free. Adaptation to feeder-free upregulated transcripts related to cell differentiation in bESC cultured in high compared to low oxygen. Transition of bESC on MEF from normoxia to 5% O2 did not alter cell morphology or growth. Interestingly, colony morphology was maintained when transitioning bESC from MEF into feeder-free in low oxygen. Furthermore, there were fewer transcriptomic changes in bESC grown on MEF compared to feeder-free in low compared to high oxygen. While low oxygen tension did not alter the pluripotency profile of bESC, it promoted transcriptional changes related to energetic metabolism and increased mitochondrial membrane potential. These findings emphasize the importance of oxygen tension for derivation, maintenance, and performance of ESC.

Keywords:  Embryonic stem cell; Metabolism; Oxygen; Pluripotency; Transcriptome

DOI:  https://doi.org/10.1242/bio.062352
Neuropsychopharmacology. 2026 Apr 30.

Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.

Simone Astori, Olivia Zanoletti, Jocelyn Grosse, Carmen Sandi.

Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-and how such adaptations shape behavior-remains poorly understood. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, which led us to hypothesize that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. To test this hypothesis, we examined how acute mitochondrial inhibition alters MSN function using mouse brain slices. Inhibition of mitochondrial complex I with the selective inhibitor rotenone reduced MSN intrinsic excitability, an effect that was counteracted by intracellular ATP replenishment. We next asked whether ATP-sensitive potassium (K-ATP) channels, canonical regulators of membrane excitability under metabolic stress, contribute to these responses. Histological analyses revealed specific expression of Kir6.2 subunits in both D1- and D2-MSNs, as compared to non-MSNs, and electrophysiological recordings showed that K-ATP channel activation blockade prevented rotenone-induced reductions in MSN excitability. In behavioral assays, complex I inhibition impaired effort-related performance, an effect that was rescued by K-ATP channel blockade. These findings identify K-ATP channels in MSNs as key mediators that sense acute changes in neuronal energy state and translate them into rapid adjustments in NAc excitability and behavior.

DOI: https://doi.org/10.1038/s41386-026-02429-8