bims-medica 2025-10-19 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–10–19
twenty-six papers selected by
Brett Chrest, Wake Forest University

Aged mice exhibit widespread metabolic changes but preserved major fluxes.
Spatial metabolic gradients in the liver and small intestine.
Now you serine, now you don't.
Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
Bioenergetics of cancer cells: insights into the Warburg effect and regulation of ATP synthase.
Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.
Metabolic Changes in Living Human Lymphoma Cells Intervening NAD+ Metabolism as Revealed by NAD(P)H-Fluorescence Lifetime Imaging and Para-Hydrogen-Induced Polarization NMR.
Nutritional strategies in the management of diffuse gliomas: A systematic review.
Nutrient allocation fuels T cell-mediated immunity.
Sex Dimorphism and Substrate Dependency of Liver Mitochondrial Bioenergetics and H2O2 Production.
Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
R103 and R115 Affinity Mutants of ATeam ATP Biosensors.
Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations.
A 'turn-on' iridium(III) complex probe for visualizing mitochondrial SO2 fluctuation in cancer cells and tumor models.
Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer.
Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival.
Visualization of oxygen profile in reconstructed human epidermis by phosphorescence-lifetime imaging microscopy using Ir(III) complex.
Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial.
Impact of Comprehensive Lifestyle Interventions on Plasma Branched-Chain Amino Acid Concentrations: A Randomized Trial.
Integrated analysis of mitochondrial ETC inhibition reveals genotype-specific heterogeneity of drug response in glioblastoma.
Classical and Modified Ketogenic Diets for Children and Young People With Drug-Resistant Epilepsy: A Reflection of International Dietetic Practice and Best Practice Recommendations for Dietitians.
Comparative Diagnostic Performance of Digital Versus Analog PET/CT for Lymph Node Metastases and Glut-1 Correlation in Resected Non-Small Cell Lung Cancer.
Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
Detection of acute myeloid leukemia and remission states using heterogeneous flow cytometry data.

Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]

Aged mice exhibit widespread metabolic changes but preserved major fluxes.

Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.

  Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.

Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
Nature. 2025 Oct 15.

Spatial metabolic gradients in the liver and small intestine.

Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.

The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.

DOI: https://doi.org/10.1038/s41586-025-09616-5
Trends Pharmacol Sci. 2025 Oct 11. pii: S0165-6147(25)00225-1. [Epub ahead of print]

Now you serine, now you don't.

Robert B Cameron, Nia G Hammond, Brandon Faubert.

  Cancer cells alter metabolic programs to support uncontrolled growth and proliferation. A new study from Scott and colleagues directly examined tumor metabolism in glioblastoma patients and discovered increased import of the amino acid serine. Excitingly, limiting serine uptake enhanced the effectiveness of chemoradiation in preclinical models of glioblastoma.

Keywords:  glioblastoma; metabolism; stable isotope tracing

DOI:  https://doi.org/10.1016/j.tips.2025.10.001
Cancer Res. 2025 Oct 15.

Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.

Horacio Cardenas, Yinu Wang, Guangyuan Zhao, Delan Xingyue Hao, Ana Maria Isac, Vanessa Hernandez, Ujin Kim, Wenan Qiang, Hao F Zhang, Daniela Matei.

Ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. Here, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin sensitive and resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin resistant cells had a lower oxygen consumption rate (OCR) and spare respiratory capacity (SRC) than sensitive cells. BRQ suppressed OCR in both sensitive and resistant but only inhibited SRC in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0043
Mol Med. 2025 Oct 13. 31(1): 311

Bioenergetics of cancer cells: insights into the Warburg effect and regulation of ATP synthase.

Valentina Del Dotto, Silvia Grillini, Riccardo Righetti, Martina Grandi, Valentina Giorgio, Giancarlo Solaini, Alessandra Baracca.

  The study reported here offers new insights into the metabolic changes associated with the Warburg effect (i.e. aerobic glycolysis) in cancer cells and into the possible role of IF1, the endogenous inhibitor of ATP synthase that preserves cellular energy when it works in reverse, hydrolyzing ATP. We investigated biochemical and main bioenergetic parameters in cell lines derived from three human tumors: osteosarcoma (143B), colon carcinoma (HCT116), and cervix carcinoma (HeLa). The combination analysis of cellular glucose consumption, lactate production, ATP-linked respiration rate, ATP level, cell culture medium acidification rate, and ROS level demonstrates that aerobic glycolysis is differently expressed by the three different types of tumor cells, although all cell types exhibited a Warburg phenotype. The superoxide anion level was found to be lower in HCT116 cells, which showed the highest ratio between oxidative phosphorylation and glycolysis rates, while ROS level was similar in all cells examined, suggesting that mitochondria in HCT116 are very efficient in both energy production and limiting their oxidative stress. Additionally, IF1 KD cells of all kinds of tumor showed higher level of ROS compared to their related IF1-expressing cells. Most of the results reported here clearly demonstrate that aerobic glycolysis is completely independent on both the level of IF1 and the IF1/ATP synthase ratio, excluding the contribution of an IF1-dependent mechanism in the metabolic shift of cancer cells towards glycolysis. Indeed, the study provides a detailed analysis of the bioenergetics of tumor cells exhibiting very different IF1/ATP synthase ratios and shows that IF1 KD cells of all tumor types had a higher level of ROS than their related IF1-expressing cells. Overall, the comprehensive picture of tumor cell bioenergetics would facilitate the identification of appropriate drugs for targeted tumor treatments, such as ATP synthase-IF1 immunotherapy that would strongly limit cellular resistance to severe hypoxia or anoxia, where IF1 plays an effective critical role.

Keywords:  ATP synthase; Aerobic glycolysis; Bioenergetics; Cancer; IF1 ; Mitochondria; ROS

DOI:  https://doi.org/10.1186/s10020-025-01378-0
ACS Chem Neurosci. 2025 Oct 16.

Region-Specific Quantification of 2-Hydroxyglutarate Enantiomers in Murine Brain during Mitochondrial Complex I Deficiency.

Richard S McCain, Gerardo G Piroli, Holland H Smith, Aman S Sumal, Paul A Grimsrud, William E Cotham, Michael D Walla, Norma Frizzell.

  The Ndufs4-/- mouse is a model of mitochondrial Complex I deficiency that contributes to altered production of the tricarboxylic acid cycle metabolites. We hypothesized that l-2-hydroxyglutarate (l-2-HG) levels would be elevated in the pathologically affected regions of the Ndufs4-/- mouse brain in parallel with metabolic acidosis. We employed a stable isotope dilution method for the concurrent quantification of l-lactate and the distinct 2-HG enantiomers in isolated mouse brain regions. While lactate levels were elevated, as expected in the Ndufs4-/- brain, the levels of l-2-HG and the enantiomer d-2-HG were markedly reduced in a region-specific manner, and this decrease was also reproduced in the Ndufs4-/- serum. The specific and reproducible decreases in 2-HG quantified in Complex I deficiency may have utility as a unique disease biomarker. Quantitative analysis of the mitochondrial proteome of the Ndufs4-/- mouse brainstem indicated an increased abundance of l-2-HG dehydrogenase, suggesting that 2-HG enantiomers are metabolized in the Ndufs4-/- mouse yielding FADH2 to alleviate the bioenergetic deficit.

Keywords:  2-hydroxyglutarate; brainstem; lactate; mass spectrometry; mitochondrial disease; neurometabolic

DOI:  https://doi.org/10.1021/acschemneuro.5c00628
Cytometry A. 2025 Oct 17.

Metabolic Changes in Living Human Lymphoma Cells Intervening NAD+ Metabolism as Revealed by NAD(P)H-Fluorescence Lifetime Imaging and Para-Hydrogen-Induced Polarization NMR.

Lea Marie Jeude, Ruth Leben, Wiebke Beninga, Yonghong Ding, Gabriele Stevanato, Stefan Glöggler, Raluca A Niesner, Dieter Kube.

Proliferating cells have a sustained high demand for regeneration of electron acceptors as nicotinamide dinucleotide (phosphate) (NAD(P)+/NAD(P)H) is involved in a number of critical redox reactions within cells. However, their analysis in living cells is still challenging. We propose that combining label-free NADH and NADPH fluorescence lifetime imaging (NAD(P)H-FLIM) and signal-enhanced nuclear magnetic resonance (NMR) spectroscopy allows new, deeper insights into changes in specific metabolic pathways in living cells. For proof of principle, NAD+-metabolism was perturbed by specific inhibition of the rate-limiting enzyme of the NAD+ "Salvage pathway" Nicotinamide phosphoribosyltransferase (NAMPT) by FK866 in RAMOS human lymphoma cells. FK866 treatment leads to NAD(H) reduction, followed by reduced RAMOS cell proliferation. The NAD(P)H-FLIM analysis revealed increased general NAD(P)H-dependent metabolic activity indicated by increased ratios of enzyme-bound to total NAD(P)H concentration upon NAMPT inhibition. More importantly, a marked reduction in lactate dehydrogenase (LDH) activity accompanied by NADPH oxidase activity increase is observed. Using signal-enhanced NMR spectroscopy a reduced flux of pyruvate to lactate catalyzed by LDH is detectable in real time in living cells. This strongly supports NAD(P)H-FLIM analysis and demonstrates that intervening in the NAD+ "Salvage pathway" can have specific and global consequences for cells. Our principle study shows how spatially-resolved metabolic imaging techniques, that is, NAD(P)H-FLIM, are complemented by real-time NMR, paving the way toward a comprehensive spatiotemporal understanding of metabolic pathways in living cells.

DOI: https://doi.org/10.1002/cyto.a.24946
Neurooncol Pract. 2025 Oct;12(5): 773-786

Nutritional strategies in the management of diffuse gliomas: A systematic review.

David Gritsch, Clara Baselga-Garriga, L Nicolas Gonzalez Castro.

   Background: Infiltrating gliomas are progressive brain tumors with an invariably fatal prognosis. Nutritional interventions, such as the ketogenic diet (KD) and caloric restriction, have been explored as adjunct therapies. This systematic review assesses the evidence for the efficacy and safety of these dietary strategies in the management of diffuse gliomas.
Methods: A systematic search was conducted in PubMed, covering studies up to February 23, 2024. Inclusion criteria were English-language clinical and observational studies that examined the impact of dietary interventions on diffuse glioma outcomes. Studies were evaluated for risk of bias using the Cochrane Risk of Bias 2 (RoB 2) tool and synthesized descriptively due to the heterogeneity of study designs and outcomes.
Results: Eighteen studies (2 randomized clinical trials [RCTs] and 16 observational studies) met the inclusion criteria. The RCTs, classified as high-quality evidence, did not demonstrate significant survival benefits from dietary interventions. Observational studies, while supporting the feasibility and safety of these interventions, provided inconsistent evidence regarding their efficacy in improving overall survival (OS) or progression-free survival (PFS). Methodological limitations, including small sample sizes, variability in dietary adherence, and patient heterogeneity, were common across studies.
Discussion: The evidence suggests that while dietary interventions like KD and caloric restriction are generally safe and feasible for diffuse glioma patients, their efficacy in improving survival outcomes remains inconclusive. Limitations such as small sample sizes and variability in adherence underscore the need for larger, well-designed trials to evaluate the clinical benefits of these interventions.

Keywords:  caloric restriction; dietary interventions; glioma management; ketogenic diet; nutritional strategies

DOI:  https://doi.org/10.1093/nop/npaf049
Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]

Nutrient allocation fuels T cell-mediated immunity.

Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

  T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.

Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
Am J Physiol Gastrointest Liver Physiol. 2025 Oct 17.

Sex Dimorphism and Substrate Dependency of Liver Mitochondrial Bioenergetics and H2O2 Production.

Devanshi D Dave, Pardis Taheri, Sri Rahavi Boovarahan, Joohyun Kim, Allen W Cowley, Said H Audi, Ranjan K Dash.

  Mitochondrial bioenergetics and H2O2 production play a central role in maintaining liver metabolic function and redox balance. Understanding sex dimorphism and substrate dependency in these mitochondrial processes is crucial for elucidating the regulatory mechanisms that govern male vs. female differences in liver physiology in health and disease. This study aimed at investigating sex-specific and substrate-dependent alterations in liver mitochondrial respiratory rates (JO2), membrane potential (ΔΨ), and H2O2 production and their metabolic regulation. Liver mitochondria were isolated from adult male and female Sprague-Dawley (SD) rats. Four substrate combinations-pyruvate+malate (PM), glutamate+malate (GM), succinate, and succinate with complex I inhibitor rotenone (SR)-were used to determine their impact on the activities of the electron transport chain (ETC) and TCA cycle complexes. ADP was added to determine the influence of substrates on oxidative phosphorylation (OxPhos). JO2 and ΔΨ were measured simultaneously using an Oroboros Oxygraph-2k respirometer with the cationic rhodamine dye TMRM. H2O2 production was measured spectrofluorometrically using the Amplex Red and Horseradish Peroxidase assay. Our results show that male and female liver mitochondria displayed distinct respiratory patterns for different substrates. GM and succinate yielded higher JO2, while PM yielded the lowest JO2. Notably, female mitochondria exhibited higher JO2 than males across all substrates. Both ΔΨ and H₂O₂ production showed substrate-dependent patterns, with females exhibiting higher values than males across all substrates. These findings reveal sex-specific differences in liver mitochondrial function, driven by substrate-dependent engagement of the ETC and TCA cycle complexes towards OxPhos, with females showing higher respiratory capacity and H2O2 production.

Keywords:  Mitochondrial bioenergetics; Oxidative phosphorylation; Oxidative stress; Reactive oxygen species; Sex differences

DOI:  https://doi.org/10.1152/ajpgi.00196.2025
Cell Metab. 2025 Oct 10. pii: S1550-4131(25)00434-6. [Epub ahead of print]

Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.

Artem Khan, Frederick S Yen, Gokhan Unlu, Nicole L DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R Gamazon, Gary J Patti, Kıvanç Birsoy.

  Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.

Keywords:  SLC25A45; SLC45A4; UNC93A; acetylglucosamine; carnitine synthesis; fasting; metabolomic GWAS; mitochondrial metabolism; polyamines; solute carrier transporters

DOI:  https://doi.org/10.1016/j.cmet.2025.09.015
Sensors (Basel). 2025 Oct 06. pii: 6180. [Epub ahead of print]25(19):

R103 and R115 Affinity Mutants of ATeam ATP Biosensors.

Autumn Cholger, Jason M Conley, Stephen A Valentino, Elaine Colomb, Olivia de Cuba, Jacob Kress, Mathew Tantama.

  Adenosine triphosphate (ATP) varies from nanomolar to millimolar levels across the physiological landscapes in which it serves as an energy carrier, phosphate donor, and purinergic signaling molecule. To measure these vastly different concentrations, genetically encoded sensors with different affinities are needed to match the particular ATP range and application. To this end, we mutagenized two key arginine residues in the ATP-binding domain of the ATeam family of sensors to explore how charge neutralization and charge reversal affect ATP affinity. As a result, we generated an extended family of affinity mutants with apparent dissociation constants ranging from sub-micromolar to millimolar. We then carried out live-cell imaging to demonstrate the utility of different affinity mutants in detecting mild versus extreme metabolic inhibition. Overall, these sensors add to the toolbox for understanding ATP dynamics in and around cells.

Keywords:  ATP biosensor; FRET; affinity mutant

DOI:  https://doi.org/10.3390/s25196180
Sci Adv. 2025 Oct 17. 11(42): eadx8662

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.

Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.

Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.

DOI: https://doi.org/10.1126/sciadv.adx8662
Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]

SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.

Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.

  Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.

Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers

DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
Biomed Pharmacother. 2025 Oct 13. pii: S0753-3322(25)00841-8. [Epub ahead of print]192 118647

Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations.

Elham Gholizadeh, Ehsan Zangene, Alun Parsons, Mika Kontro, Caroline A Heckman, Mohieddin Jafari.

  Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal expansion of myeloid precursor cells. Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model. The study integrates real-time cell viability assays, xenograft imaging, and genetic analyses and relates responses to mutational profiles and benchmarks against first line treatment (venetoclax based combinations), the current standard for older and unfit AML. Both combinations outperformed or matched venetoclax-based comparators, with LS markedly reducing viability and RU showing robust efficacy in AML cell lines. In zebrafish, LS and RU suppressed leukemic burden with zero mortality and with modest effects on embryo length, indicating supportive but preliminary tolerability under the conditions tested. Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts.

Keywords:  Acute Myeloid Leukemia (AML); Combination Therapy; Drug Resistance; TP53 Mutation; Targeted Therapy; Zebrafish Xenograft Model

DOI:  https://doi.org/10.1016/j.biopha.2025.118647
Dalton Trans. 2025 Oct 15.

A 'turn-on' iridium(III) complex probe for visualizing mitochondrial SO2 fluctuation in cancer cells and tumor models.

Si-Yu Chen, Meng-Sen Chen, An-Li Liu, Gao-Nan Li, Fa-Biao Yu, Zhi-Gang Niu.

Mitochondrial sulfur dioxide (SO2) plays critical biological roles in physiological processes. Notably, abnormal endogenous SO2 levels serve as potential biomarkers for early diagnosis of tumors. Therefore, visual detection of SO2 in cancer cells and tumor models is a subject of significant interest. A 'turn-on' iridium(III) complex probe (Ir-CHO) was designed and synthesized, utilizing 2-phenylpyridine (ppy) as the main ligand and 2-(pyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (PIP-CHO) as the ancillary ligand, for identifying SO2 in living HeLa cells and tumors through bioimaging. The probe exhibits some outstanding properties, including high phosphorescence quantum yield (31.1%), microsecond lifetime (0.61 μs), relatively low detection limit (0.68 μM), rapid response (<1 min), excellent photostability (>60 min), high selectivity and specificity, low cytotoxicity, and mitochondrial targeting ability (PCC = 0.805). Based on these properties, the probe was successfully applied to visualize endogenous and exogenous SO2 in living cells and effectively distinguish between normal mice and tumor mice with negligible systemic toxicity. All the results suggest that this new probe Ir-CHO could monitor SO2 derivatives in real time within tumor microenvironment research, highlighting its promising diagnostic potential for future clinical and biomedical applications.

DOI: https://doi.org/10.1039/d5dt01854d
Cancer Cell Int. 2025 Oct 17. 25(1): 362

Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer.

Luis Silva, Nicholas Skiados, Nikitha Murugavel, Karen Cover, Nastassja Luna, Manish K Gupta, Stephanie C Contreras, Terrence E O'Brien, Wen Cai Zhang.

   BACKGROUND: Lung cancer treatment efficacy remains a challenge due to limited therapeutic targets. Succinate dehydrogenase (SDH) enzyme, a crucial enzyme linking the citric acid cycle and the electron transport chain, is implicated in cancer metabolism. While existing compounds target metabolic diseases in vitro, SDH-targeted therapy for lung cancer remains elusive.
METHODS: We assessed SDH expression levels in non-small cell lung (NSCLC) tissues and cell lines. Leveraging AtomNet® technology for compound identification, coupled with mitochondria- and cell-based enzyme activity assays, we discovered new SDH inhibitors. Using 2D monolayer, 3D organoid culture, and assays for cell viability, migration, mitochondrial reactive oxygen species, oxygen consumption rate, succinate accumulation, and apoptosis, we elucidated their mechanism targeting lung malignancy.
RESULTS: SDH subunits were found to be overexpressed in NSCLC tissues compared to tumor-adjacent normal tissues. Two new SDH inhibitors were identified from 96 predicted candidates. Cellular thermal shift assay confirmed direct binding of these small molecules to SDH subunits in lung cancer cells. Mechanistically, treatment increased cellular and mitochondrial reactive oxygen species, succinate accumulation, and induced apoptosis by damaging mitochondria and DNA, while modulating SDH protein expression. Functionally, these molecules reduced growth, migration, and 3D organoid formation in lung cancer cell lines in vitro, both short and long term.
CONCLUSIONS: Our SDH inhibitors halt tumor growth and migration by targeting key substrate binding sites, showing superior efficacy over existing small molecule antagonists. They also modulate SDH protein expression, suggesting a promising dual-targeting strategy for cancer therapy. This study sheds light on SDH function in cancer-related metabolic dysfunction and underscores the potential of SDH modulation as a therapeutic strategy for lung cancer and beyond.

Keywords:  Cell apoptosis; Non-small cell lung cancer; Oxygen consumption rate; Reactive oxygen species; SDH; Small molecule inhibitor

DOI:  https://doi.org/10.1186/s12935-025-04002-7
Cells. 2025 Oct 08. pii: 1557. [Epub ahead of print]14(19):

Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival.

Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea.

  The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.

Keywords:  BCL-XL; chemotherapy; oxidative phosphorylation; quiescence; triple-negative breast cancer

DOI:  https://doi.org/10.3390/cells14191557
Sci Rep. 2025 Oct 15. 15(1): 36008

Visualization of oxygen profile in reconstructed human epidermis by phosphorescence-lifetime imaging microscopy using Ir(III) complex.

Misaki Ochiai-Noguchi, Aoi Horikoshi, Seina Hirakata, Toshitada Yoshihara.

  Reconstructed human epidermis (RHE) is a useful experimental tool for evaluating the effects of various stimuli on the skin. Here, we present a method to visualize the partial pressure of oxygen in RHE with cellular-level spatial resolution by means of confocal phosphorescence-lifetime imaging microscopy (PLIM) with a cell-permeable phosphorescent probe, BTPDM1 (an iridium-based cationic lipophilic dye). Z-stack PLIM images of RHE revealed an oxygen partial pressure gradient in the direction of differentiation, with a decrease in oxygen levels from the basal layer to the cornified layer. FCCP (carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone), an uncoupler of mitochondrial oxidative phosphorylation, significantly decreased pO₂, suggesting that changes in mitochondrial respiration may contribute to the O₂ concentration gradient in RHE. Antimycin A (Ant A), an inhibitor of mitochondrial respiration, decreased expression of the differentiation markers filaggrin and loricrin, indicating that mitochondrial respiration is essential for normal epidermal maturation. In 2D keratinocyte cultures, addition of calcium as a differentiation inducer led to an increase in mitochondrial oxygen consumption and oxidative phosphorylation. These results indicate that oxygen imaging is an effective method for evaluating not only mitochondrial respiration status, but also the differentiation state of reconstructed human epidermis.

Keywords:  Differentiation; Iridium(III) complex; Keratinocyte; Oxygen; Phosphorescence lifetime; Skin

DOI:  https://doi.org/10.1038/s41598-025-19891-x
Lancet Haematol. 2025 Oct 08. pii: S2352-3026(25)00254-6. [Epub ahead of print]

Enasidenib plus venetoclax in patients with IDH2-mutated relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome (ENAVEN-AML): a multicentre, single-arm, phase 1b/2 trial.

Guillaume Richard-Carpentier, Gopila Gupta, Charina Koraksic, Severine Cathelin, Lisa Wang, Aniket Bankar, Marta Davidson, Vikas Gupta, Dawn Maze, Mark D Minden, Tracy Murphy, Aaron D Schimmer, Andre C Schuh, Hassan Sibai, Karen Yee, Courtney D DiNardo, Joseph Brandwein, Caroline J McNamara, Steven M Chan.

BACKGROUND: Enasidenib, a mutant IDH2 inhibitor, is used to treat IDH2-mutated acute myeloid leukaemia (AML). Preclinical studies have demonstrated synergy between enasidenib and venetoclax, a BCL2 inhibitor, in IDH2-mutated AML. The aim of this study was to evaluate the safety and activity of enasidenib plus venetoclax in patients with relapsed or refractory IDH2-mutated AML or myelodysplastic syndromes (MDS).
METHODS: The ENAVEN-AML study was a single-arm, phase 1b/2 trial conducted at two centres in Canada. Patients were eligible to participate if they were 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 to 2, had a confirmed IDH2 mutation (affecting Arg140 or Arg172), and had AML or MDS that was refractory or had relapsed after at least one line of treatment. Patients were treated with venetoclax 400 mg orally daily with a 3-day dose ramp-up starting on cycle 1 day 1 and enasidenib 100 mg orally daily starting on cycle 1 day 15. The primary endpoint of the phase 1b portion was safety, which included dose-limiting toxicity and the frequency and severity of treatment-emergent adverse events (TEAEs), as well as determining the maximum tolerated dose and recommended phase 2 dose. The primary objective of the phase 2 portion was to assess preliminary activity, with overall response rate by intention-to-treat as the primary endpoint. Assessment of safety and activity were determined on the pooled analysis data from the phase 1 and 2 studies. The ENAVEN-AML study is registered with ClinicalTrials.gov (NCT04092179) and is completed.
FINDINGS: From Nov 12, 2020, to July 5, 2022, the study enrolled 27 patients (13 in phase 1b, 14 in phase 2) and the median follow-up was 20·2 months (IQR 15·0-23·0) at the data cutoff on Sept 30, 2023. The median age was 70 years (IQR 55-76); 16 (59%) of 27 patients were male, 11 (41%) female, and 19 (70%) White. 26 patients had relapsed or refractory AML, and one patient had relapsed MDS. The most common grade 3 or worse TEAEs were febrile neutropenia (n=11, 41%), infections (n=8, 30%), thrombocytopenia (n=7, 26%), pneumonia (n=6, 22%), sepsis (n=5, 19%), and anaemia (n=5, 19%). One case of IDH inhibitor-associated differentiation syndrome was observed. Serious adverse events were reported in 17 (62%) of 27 patients, most commonly infections (n=11, 41%) and intracranial bleeding (n=5, 19%). No dose-limiting toxicities or treatment-related deaths were observed. The recommended phase 2 dose was 400 mg daily for venetoclax and 100 mg daily for enasidenib. Of the 26 patients with AML, the overall response rate was 62% (95% CI 41-80; 16 of 26), with 13 (50%) of 26 having complete remission. The only patient with MDS did not respond to enasidenib plus venetoclax.
INTERPRETATION: Enasidenib plus venetoclax is safe, with no unexpected TEAEs or treatment-related deaths, and shows preliminary activity in patients with relapsed or refractory IDH2-mutated AML and MDS.
FUNDING: AbbVie and Bristol Myers Squibb.

DOI: https://doi.org/10.1016/S2352-3026(25)00254-6
Am J Clin Nutr. 2025 Oct 15. pii: S0002-9165(25)00612-4. [Epub ahead of print]

Impact of Comprehensive Lifestyle Interventions on Plasma Branched-Chain Amino Acid Concentrations: A Randomized Trial.

Yu Jin Lim, Rob M van Dam.

   BACKGROUND: Elevated plasma branched-chain amino acid (BCAA) concentrations are associated with a higher risk of type 2 diabetes and cardiovascular diseases. Lifestyle interventions have been proposed as a strategy to manage plasma BCAA concentrations, but evidence of their effectiveness is limited.
OBJECTIVE: We investigated the effects of comprehensive lifestyle interventions on plasma BCAA concentrations over six months and associations between changes in Body Mass Index (BMI), physical fitness, and dietary factors and plasma BCAA changes METHODS: The PREMIER study was a randomized trial of the effects of behavioral lifestyle interventions. The interventions included counseling on diet, exercise, and weight loss ('Established'), a similar intervention with additional guidance to follow Dietary Approaches to Stop Hypertension ('Established plus DASH'), and an advice-only control group. We analyzed data from 713 male and female adult participants during the 6-month intervention period. Data and biospecimens were obtained through the NHLBI BioLINCC repository, and plasma BCAA concentrations were measured using NMR spectroscopy. Multiple linear regression was used to assess the association between intervention groups and BCAA concentrations.
RESULTS: The Established (-7.19 μmol/L; 95% CI 17.45, 3.08) and Established plus DASH (-8.70 μmol/L; 95% CI -18.95, 1.55) interventions were associated with non-significant decreases in BCAA concentrations compared with the control group. Changes in BMI were correlated with changes in BCAA concentrations during the trial (partial Pearson r=0.24, p<0.001). Although changes in fitness and fiber intake were also significantly correlated with changes in BCAA concentrations, adjustment for BMI attenuated these correlations. Changes in the DASH and healthy plant-based diet indices and BCAA and protein intakes were not significantly correlated with plasma BCAA changes.
CONCLUSION: Weight loss resulting from lifestyle interventions was associated with reductions in plasma BCAA concentrations. Improvements in fitness and diet composition were not associated with changes in BCAA concentrations independent of weight loss.
CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT00000616).

Keywords:  branched-chain amino acids; dietary patterns; fitness; randomized controlled trial; weight loss

DOI:  https://doi.org/10.1016/j.ajcnut.2025.10.008
Biochem Biophys Res Commun. 2025 Oct 13. pii: S0006-291X(25)01514-1. [Epub ahead of print]787 152798

Integrated analysis of mitochondrial ETC inhibition reveals genotype-specific heterogeneity of drug response in glioblastoma.

Madhuri Belekar, Vijendra Kavatalkar, Ritu Yadav, Anu Raghunathan.

  Glioblastoma (GBM) is among the most aggressive brain cancers, driven by genetic diversity and resistance to therapy. Mitochondrial metabolism-and in particular the electron transport chain (ETC)-has emerged as both a key weakness and a source of variable drug response. To investigate this, we integrated constraint-based metabolic modeling (CBM), high-resolution drug profiling, and genomic sequencing across three GBM cell models: LN229, U87MG, and neurospheres (NSP). Modeling predicted distinct ETC vulnerabilities, which were confirmed experimentally using inhibitors against Complexes I-V. Sensitivity to rotenone varied sharply: NSP cells were most vulnerable (IC50 = 0.007 μM), LN229 showed intermediate sensitivity (0.021 μM), and U87MG remained highly resistant (1.816 μM). Across inhibitors, LN229 consistently showed steep dose-response slopes, U87MG maintained flat curves, and NSP displayed selective weaknesses. By incorporating slope (m) and Instantaneous Inhibitory Potential (IIP), median-effect analysis captured dynamic drug-response behaviour's that IC50 values alone overlooked. Genomic sequencing revealed striking differences in mutational burden: U87MG and NSP carried 354 and 307 single nucleotide polymorphisms (SNPs), respectively, compared with 141 in LN229. Several non-synonymous mutations were directly linked to altered drug sensitivity, including L194S, Y50 N, and L46V in LN229; S456L, A466T, and Y629F in U87MG; and the NSP-specific R159Q. Notably, mutations near catalytic sites correlated with changes in slope and IIP, providing mechanistic insight into therapeutic response. Together, these results show how genetic variation reshapes ETC function and drug sensitivity in GBM, offering a predictive framework for mutation-informed, personalized therapy.

Keywords:  Drug dose response; Electron transport chain; Glioblastoma; IC50 value; Instantaneous inhibitory potential; Mitochondrial genome

DOI:  https://doi.org/10.1016/j.bbrc.2025.152798
J Hum Nutr Diet. 2025 Oct;38(5): e70129

Classical and Modified Ketogenic Diets for Children and Young People With Drug-Resistant Epilepsy: A Reflection of International Dietetic Practice and Best Practice Recommendations for Dietitians.

Best Practice Recommendations Advisory Group, on behalf of the Ketogenic Dietitians Research Network

   INTRODUCTION: A global need was identified for a practical, comprehensive tool to guide dietitians internationally working in ketogenic diet therapy (KDT), detailing all aspects of dietetic management. The aim of this project was to develop best practice recommendations for the dietetic management of classical and modified ketogenic diets in the management of epilepsy and neurometabolic conditions.
METHODS: Expert ketogenic dietitians from six continents were invited to participate as members of either a core working group or advisory group. A systematic literature review was conducted, covering all aspects of dietetic management, from patient selection to diet discontinuation. To complement this, an international survey was distributed to ketogenic dietitians currently delivering classical and modified ketogenic diets, structured around the same key themes.
RESULTS: A total of 111 dietitians responded to the survey, representing six continents. For each theme, findings from the literature were presented alongside survey responses. Recommendations were generated where ≥ 75% consensus was achieved. In areas where this threshold was not met, the most commonly reported practices were presented, acknowledging the variety of international approaches.
CONCLUSION: These are the first international best practice recommendations specifically for ketogenic dietitians and nutrition healthcare professionals supporting children following medically advised classical and modified ketogenic diets. The recommendations are informed by both published evidence and prevailing international dietetic practice, whilst recognizing the variety in clinical delivery.

Keywords:  classical ketogenic diet; clinical; dietetic; epilepsy; guidelines; modified ketogenic diet

DOI:  https://doi.org/10.1111/jhn.70129
Cancer Manag Res. 2025 ;17 2319-2336

Comparative Diagnostic Performance of Digital Versus Analog PET/CT for Lymph Node Metastases and Glut-1 Correlation in Resected Non-Small Cell Lung Cancer.

Katsuhiko Shimizu, Yoshihiko Fukukura, Shinsuke Saisho, Yuji Nojima, Shogo Takeuchi, Takashi Matsutani, Hiroki Sugiyama, Masao Nakata.

   Background: Recent innovations in technology have significantly advanced the imaging capabilities of positron emission tomography/computed tomography (PET/CT). Digital PET/CT provides sensitive and high-resolution imaging and can improve the detection of small lesions as compared to conventional (analog) PET/CT. This study aimed to compare the diagnostic performance of digital versus analog PET/CT for detecting lymph node metastases and to assess the maximum standardized uptake (SUVmax) values in patients with resected non-small cell lung cancer (NSCLC).
Methods: We enrolled a total of 103 patients with lung adenocarcinoma or squamous cell carcinoma who had undergone preoperative PET/CT in either analog or digital scanners. The primary endpoint was comparison of the diagnostic performance of the two modalities for lymph node metastasis, and the secondary endpoints were comparison of the SUVmax values and correlation of the SUVmax values with the Glut-1 (glucose transporter type 1) expression.
Results: Of the 103 patients enrolled in the study, 61 had undergone analog PET/CT, and 42 had undergone digital PET/CT. Significantly higher SUVmax values on digital as compare with analog PET/CT were obtained for cT1b tumors (D/A ratio = 3.42, p = 0.002) as well as cT1c tumors (D/A ratio = 2.10, p < 0.001). However, no significant difference in SUVmax values between the two types of PET/CT was obtained for tumors exceeding 3.0 cm in diameter. A stronger correlation was found between tumor Glut-1 expression and the SUVmax values obtained digital PET/CT as compared with the values obtained with analog PET/CT. Digital PET/CT also showed a higher sensitivity (71.4% vs 37.5%) for detecting lymph node metastases, although the specificity was slightly lower (88.6% vs 96.2%), and the overall accuracy was comparable (85.7% vs 88.5%) between the two types of scanners. False-positive lymph nodes on digital PET/CT were obtained in conditions such as pneumoconiosis and anthracosis, while false-negatives results were obtained in conditions such as micrometastases and/or low lymph node Glut-1 expression.
Conclusion: These results suggest that digital PET/CT shows improved diagnostic sensitivity and that the results of digital PET/CT are better correlated with tumor metabolic activity, which results in improved detection of lymph node metastases. These results support the clinical usefulness of digital PET/CT for optimizing perioperative strategies and increasing diagnostic confidence in the management of NSCLC. Future multicenter prospective studies and a standardized redefinition of SUVmax are urgently needed to validate our findings and to establish more reliable clinical application of digital PET/CT in patients with lung cancer.

Keywords:  Glut-1; SUVmax; digital PET/CT; lymph node metastases

DOI:  https://doi.org/10.2147/CMAR.S542593
Front Cell Dev Biol. 2025 ;13 1650462

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.

Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.

  Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

Keywords:  NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism

DOI:  https://doi.org/10.3389/fcell.2025.1650462
Front Oncol. 2025 ;15 1638074

Detection of acute myeloid leukemia and remission states using heterogeneous flow cytometry data.

Renjun Bao, Ming Feng, Mian Wang, Yunkai Liu, Liang Hu, Yonghua Yao.

   Introduction: Acute myeloid leukemia (AML) is a hematological malignancy that requires accurate diagnosis and continuous monitoring to guide effective treatment. Flow cytometry is widely used because it enables the detection of minimal residual disease. However, current methods often rely on uniform marker panels, overlooking the heterogeneity that arises when different markers or staining protocols are used across patients. In addition, remission states are frequently neglected, despite their clinical importance for disease management and prognosis.
Methods: To address these challenges, we developed a machine learning-based classification framework that integrates heterogeneous flow cytometry data. A dataset comprising 53 markers was collected, and six different machine learning classifiers were trained to distinguish between AML, complete remission (AML-CR), and normal samples. Model performance was evaluated using accuracy, precision, recall, F1 score, and area under the ROC curve (AUC).
Results: Among the classifiers evaluated, the Random Forest model demonstrated the highest performance, achieving an accuracy of 94.92%, an F1-score of 94.13%, a precision of 94.58%, a recall of 93.74%, and an AUC of 94.83%. These results indicate that machine learning can effectively classify AML and remission states from heterogeneous flow cytometry data.
Discussion: This study highlights the value of machine learning in overcoming limitations of traditional flow cytometry analysis. By accommodating marker heterogeneity and incorporating remission states, the proposed framework provides a more robust and clinically relevant tool for AML diagnosis and monitoring. The findings suggest that machine learning models, particularly Random Forest, hold strong potential for improving precision in hematological diagnostics. The code for this study is publicly available at https://zenodo.org/records/15110287.

Keywords:  acute myeloid leukemia; diagnostic model; feature importance analysis; flow cytometry; machine learning

DOI:  https://doi.org/10.3389/fonc.2025.1638074