bims-medica 2026-02-08 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–02–08
eighteen papers selected by
Brett Chrest, Wake Forest University

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.
ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.
Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
Glutamine Dependence Is Not a Cancer-specific Vulnerability in Contrast to Methionine Dependence.
Inhibition of TRAP1 in the C-terminal domain influences mitochondria properties and breast cancer cell metabolism.
The impact of the ketogenic diet on the lipid profile in adults: A comprehensive review and meta-regression analysis of randomized controlled trials.
Rewired Neuroactive Ligand-Receptor Signaling Confers Adaptive Resistance to BCL-2 Inhibition in AML.
Metabolic responses to 48-hour fasting and refeeding in adults with and without obesity.
SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.
Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.
Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression.
Selective small molecule targeting of KDM4 as a therapeutic strategy to reduce proliferation of acute myeloid leukaemia.
Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
Gliomas with succinate dehydrogenase deficiency: A case series and brief review of the literature of oncometabolite-driven gliomagenesis.
Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.

bioRxiv. 2026 Jan 16. pii: 2026.01.15.699810. [Epub ahead of print]

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.

Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.

Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed an intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

DOI: https://doi.org/10.64898/2026.01.15.699810
Mol Metab. 2026 Feb 03. pii: S2212-8778(26)00009-8. [Epub ahead of print] 102325

Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.

Andres F Ortega, Cha Mee Vang, Ferrol I Rome, Kaitlyn M Andreoni, Aiden M Phoebe, Alisa B Nelson, Peter A Crawford, James J Galligan, Stanley Ching-Cheng Huang, Curtis C Hughey.

  Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (∼70-fold), serine concentration (∼2-fold), and 13C-serine (∼20-fold) following an intravenous infusion of [U-13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.

Keywords:  De novo serine synthesis; Glucose homeostasis; Liver intermediary metabolism; Sulfur amino acid restriction

DOI:  https://doi.org/10.1016/j.molmet.2026.102325
Cancer Res. 2026 Feb 04. OF1-OF14

ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.

Joanna Koh, Chengheng Liao, Michelle Shu Wen Ng, Jing Han Hong, Hong Lee Heng, Dan Y Gui, Zhenxun Wang, Benjamin Yan-Jiang Chua, Zhimei Li, Radoslaw M Sobota, Lye Siang Lee, Jabed Iqbal, Kevin Junliang Lim, Divya Bezwada, Ralph J DeBerardinis, Gertrud Steger, Jianhong Ching, Patrick Tan, Bin Tean Teh, Qing Zhang, Xiaosai Yao.

Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, ZNF395 depletion resulted in reduced TCA cycle intermediates and their derivatives, including amino acids, glutathione, and pyrimidine nucleotides, leading to impaired mitochondrial respiration. Restoration of mitochondrial complex I function and GLS expression partially rescued the effects of ZNF395 depletion on ccRCC tumor growth. Together, this study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
SIGNIFICANCE: ZNF395 and HIF are complementary mediators of hypoxia-induced metabolic reprogramming and therapeutic targets in VHL-deficient kidney cancer, with the former regulating glutamine metabolism and the latter regulating glucose metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4745
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf223

Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.

Mark C Dougherty, Hashim S Syed, Linjing Xu, S John Liu, David R Raleigh, Adam J Rauckhorst, Eric B Taylor, Marlan R Hansen.

   Background: Although schwannomas are common and benign, their growth patterns are often hard to predict. Currently, surgery and radiotherapy are the only standard treatments. Since metabolites are the end products of genes and proteins, metabolomics may reveal downstream tumor features in ways that other -omics cannot. Here, we use metabolomic profiling and stable isotope tracing to characterize primary human schwannomas and describe their changes following radiation in patient-derived xenografts.
Methods: Schwannomas collected during surgical resection underwent metabolomic profiling with gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (N = 44) as well as DNA methylation profiling (N = 29). Large tumors were also implanted subcutaneously in athymic mice as patient-derived xenografts. Mice were randomized to radiation treatment or control 4-6 weeks post-implantation. Xenografts were harvested 72 h after radiation for metabolomic profiling (N = 53). Another group of xenografts (N = 33) was injected with U-13C-glutamine prior to tumor harvest for stable isotope tracing.
Results: The schwannoma metabolome differs from that of Schwann cells, and metabolomics-based clustering of schwannomas resembles DNA methylation-based classification. In xenografts, radiation decreases cellular proliferation and produces small but detectable changes to the tricarboxylic acid (TCA) cycle and nucleotide metabolism. 13C-glutamine tracing shows that schwannomas can produce urea cycle intermediates, TCA cycle intermediates, cytosine monophosphate (CMP), and cytosine triphosphate from glutamine even after radiation. CMP was the only metabolite with altered 13C uptake following radiation.
Conclusions: Schwannomas have distinct metabolic signatures compared to the Schwann cells from which they originate. Schwannoma xenograft metabolism is surprisingly robust to radiotherapy, and xenografts readily incorporate glutamine into the TCA cycle, urea cycle, and pyrimidine synthesis.

Keywords:  NF2; metabolomics; radiation; schwannoma

DOI:  https://doi.org/10.1093/noajnl/vdaf223
Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]

Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.

Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.

  Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.

Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
Anticancer Res. 2026 Feb;46(2): 749-755

Glutamine Dependence Is Not a Cancer-specific Vulnerability in Contrast to Methionine Dependence.

Yuta Miyashi, Kohei Mizuta, Yohei Asano, Byung Mo Kang, Jin Soo Kim, Qinghong Han, Shukuan Li, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.

   BACKGROUND/AIM: Glutamine (GLN) addiction has been proposed as a cancer vulnerability and a therapeutic target. However, the glutamine requirement of normal cells is poorly understood. In the present study, we used a unique co-culture model to study the glutamine requirement of cancer cells compared to normal cells co-cultured together.
MATERIALS AND METHODS: The human fibrosarcoma cell line HT1080 and normal human fibroblasts HS27 were co-cultured in 12-well dishes seeded with equal numbers of cells of each type. Additionally, HS27 cells were cultured alone in 6-well plates. The cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) which did not contain GLN, methionine (MET), or cystine (CYS). 150 μM L-cystine 2HCl was added to all media. Co- and mono- cultures were grown under the following conditions: Complete medium (GLN 4 mM and MET 100 μM); MET restriction [Methionine restriction (MR), GLN 4 mM and MET 0 μM]; GLN restriction [Glutamine restriction (GR), GLN 0 mM and MET 100 μM] and MR+GR (GLN 0 mM and MET 0 μM). Cells were observed under phase-contrast and fluorescence microscopy for seven days. ImageJ was used to compare the three groups: MR, GR and MR+GR.
RESULTS: In complete DMEM, HT1080 fibrosarcoma cells dominated HS27 normal fibroblasts in co-culture. Under MR, HT1080 cells became mostly non viable, but HS27 cells remained viable. Under GR and MR+GR, both HT1080 and HS27 cells became mostly non-viable. Monoculture experiments showed that normal cells survived under MR but not GR.
CONCLUSION: GR is not a cancer-specific vulnerability, while MR is. Therefore, GR is not a promising cancer-therapy strategy.

Keywords:  Glutamine restriction; Hoffman effect; Warburg effect; cancer; cancer cells; co-culture; methionine addiction; methionine restriction; normal cells; vulnerability

DOI:  https://doi.org/10.21873/anticanres.17984
Biomed Pharmacother. 2026 Feb 02. pii: S0753-3322(26)00092-2. [Epub ahead of print]196 119060

Inhibition of TRAP1 in the C-terminal domain influences mitochondria properties and breast cancer cell metabolism.

Clélia Mathieu, Jessica Ristow Branco, Patricia Zancan, Catherine Brenner, Samir Messaoudi, Elias Fattal, Juliette Vergnaud.

  Breast cancers are characterized by complex energy metabolisms involving the Warburg effect but also mitochondria, although this area is not yet well understood. Tumor cells are particularly flexible by choosing oxidative phosphorylation (OXPHOS) or glycolysis depending on the needs and aggressiveness. Within the mitochondria, a HSP90-chaperone protein, TRAP1, exerts regulatory effects on several vital functions such as OXPHOS, production of reactive oxygen species and apoptosis by interacting with members of the respiratory chain or the mPTP. However, not all of its roles have yet been elucidated. Here, we propose to modulate TRAP1 functions using a mitochondriotropic molecule (containing triphenylphosphonium) targeting its C-terminal domain, 6BrCaQ-C10-TPP, in breast tumor cells. Its blocks proliferation with no massive apoptosis, after 24 h of treatment, and induces dissipation of the mitochondrial membrane potential. 6BrCaQ-C10-TPP also appears to modulate regulators of epithelial-mesenchymal transition (Snail and ZEB1) without a common response in all cell lines. Furthermore, the chaperone machinery is affected with a decrease of HSF1 and HSP70, but without degradation of HSP90 or TRAP1, while decreasing the levels of SDH-A and/or SDH-B, partner of TRAP1. Finally, short-term treatments (1 and 3 h) with 6BrCaQ-C10-TPP modify energy metabolism by promoting glycolysis. In conclusion, modulation of TRAP1 on the C-terminal domain by 6BrCaQ-C10-TPP exerts a cell-line dependent anti-tumor effect by modulating major mitochondrial functions in vitro. The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.

Keywords:  Breast cancer; Chaperone protein; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.biopha.2026.119060
Endocr Pract. 2026 Jan 30. pii: S1530-891X(26)00026-1. [Epub ahead of print]

The impact of the ketogenic diet on the lipid profile in adults: A comprehensive review and meta-regression analysis of randomized controlled trials.

Chaoyue Chang, Yuxia Liu, Pejman Rohani, Navideh Khodadadi, Kousalya Prabahar, Mohammad Hassan Sohouli.

   OBJECTIVES: The impact of the ketogenic diet (KD) on lipid metabolism remains inconclusive. To address this gap, we conducted a meta-regression analysis of randomized controlled trials (RCTs) to evaluate the overall influence of KD on lipid profile parameters in adults.
METHODS: A comprehensive search of five major electronic databases was carried out using predefined keywords to identify RCTs assessing the effects of KD on lipid outcomes. Pooled weighted mean differences with 95% confidence intervals were calculated employing a random-effects model.
RESULTS: Sixty-two studies were analyzed. The meta-analysis results from the included randomized controlled trials indicated a significant decrease in triglyceride (TG) levels (WMD: -19.96 mg/dl, 95% CI: -26.10 to -13.81) and the TG/high-density lipoprotein-cholesterol (HDL-C) ratio (WMD: -0.31, 95% CI: -0.49 to -0.12), despite a notable increase in HDL-C (WMD: 3.61 mg/dl, 95% CI: 1.44 to 5.57), low-density lipoprotein-cholesterol (LDL-C) (WMD: 8.49 mg/dl, 95% CI: 5.45 to 11.52), and total cholesterol (TC) (WMD: 8.14 mg/dl, 95% CI: 3.41 to 12.88) concentrations following KD compared to the control group. However, LDL-C levels increased by 8.49 mg/dL, which may carry potential adverse implications.Furthermore, the findings indicated a linear correlation between alterations in HDL-C and the duration of KD intervention.
CONCLUSIONS: The ketogenic diet significantly improves triglycerides and HDL-C but also leads to modest increases in LDL-C. Given the lack of long-term cardiovascular outcome data, these findings should be interpreted with caution.

Keywords:  Cardiovascular diseases; Dyslipidemia; Ketogenic diet; Low-carbohydrate diet; Meta-analysis

DOI:  https://doi.org/10.1016/j.eprac.2026.01.009
Res Sq. 2026 Jan 12. pii: rs.3.rs-8427312. [Epub ahead of print]

Rewired Neuroactive Ligand-Receptor Signaling Confers Adaptive Resistance to BCL-2 Inhibition in AML.

Hiroaki Koyama, Sachiko Seo, William Tse, Sicheng Bian, Shujun Liu.

A major challenge in treating AML with the BCL-2 inhibitor venetoclax is the frequent development of drug resistance, which diminishes therapeutic efficacy and leads to patient death. The fundamental mechanisms underlying this resistance are not fully understood. Here, we established venetoclax-resistant cell models of AML that propagate even when the levels of BCL-2, MCL-1, cleaved PARP, and cleaved caspase-9 are reduced, suggesting a BCL-2-independent resistance mechanism. Compared to sensitive cells, resistant Kasumi-1 (VENK) and MV4-11 (VENM) cells exhibit enhanced proliferation both in vitro and in vivo , forming larger and more numerous spheroids and colonies, and displaying higher tumorigenicity in mice. RNA sequencing and KEGG pathway analysis identified the neuroactive ligand-receptor interaction (NLRI) pathway as a key vulnerability in both resistant cell lines. While the NLRI pathway contains numerous altered genes, CHRNB4 is the only gene commonly shared and significantly downregulated in both VENK and VENM cells and tumors. Enforced expression of CHRNB4 in resistant cells with low basal expression impaired cell adhesion and colony formation. Clinically, CHRNB4 downregulation is associated with poor AML patient overall survival and predicts a diminished response to venetoclax treatment. This study identifies the NLRI pathway as a crucial vulnerability in venetoclax resistance and unveils CHRNB4 as a promising predictive biomarker for treatment response. These results suggest that targeting the NLRI pathway represents a novel strategy for developing next-generation therapies to improve the poor outcomes of current combination treatments.

DOI: https://doi.org/10.21203/rs.3.rs-8427312/v1
Appl Physiol Nutr Metab. 2026 Feb 06.

Metabolic responses to 48-hour fasting and refeeding in adults with and without obesity.

Roderick E Sandilands, Helena Neudorf, Spencer Ursel, Hillary Shaba, Darren Barg, Erica Vaz, Patricia Schimweg, Hashim Islam, Jonathan P Little.

BACKGROUND: Metabolic flexibility - the ability to adapt substrate utilization to availability - is commonly impaired in individuals with obesity. While short-term fasting promotes lipid utilization, it may lead to subsequent metabolic inflexibility by blunting carbohydrate metabolism upon refeeding. However, the extent to which this differs in obesity remains unknown.
OBJECTIVE: To examine if a 48-hour fast differentially affects substrate utilization during refeeding in individuals with and without obesity.
METHODS: Adults classified as lean (n = 16) or with obesity (n = 16) (8 males and 8 females per group) completed a 48-hour fast followed by a mixed meal tolerance test (MMTT). Respiratory exchange ratio (RER), glucose, β-hydroxybutyrate (BHB), insulin, and free fatty acid (FFA) levels were measured at baseline, after 48-hours of fasting, and 1 and 2 hours postprandially to assess substrate utilization.
RESULTS: Individuals with obesity exhibited baseline hyperinsulinemia despite similar glucose levels when compared to lean individuals. Fasting reduced circulating insulin and glucose, and elicited a shift toward fat oxidation in both groups, reflected by decreased RER and elevated FFAs (P < 0.001). Despite similar FFA concentrations, individuals with obesity demonstrated lower BHB concentrations (P < 0.001) following the fast when compared to their lean counterparts. Upon refeeding, individuals with obesity demonstrated lower 2-hour postprandial glucose excursions compared to lean participants (P < 0.001).
CONCLUSION: The presence of obesity may elicit a paradoxical advantage in restoring carbohydrate metabolism following short-term fasting. We speculate that fasting may alleviate basal hyperinsulinemia-induced insulin resistance, which partially counteracts fasting-induced glucose intolerance.
TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov (NCT05886738).

DOI: https://doi.org/10.1139/apnm-2025-0447
Nat Metab. 2026 Feb 06.

SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.

Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.

Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.

DOI: https://doi.org/10.1038/s42255-026-01455-6
Nat Commun. 2026 Feb 05.

Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.

Zhenlong Li, Rui Ma, Hejun Tang, Ningyuan Liu, Jianying Zhang, Guido Marcucci, Michael A Caligiuri, Jianhua Yu.

Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34+CD38+ to CD34-CD38+ cells and blocks the differentiation of LSCs (CD34+CD38-) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34-CD38+ to CD34-CD38- cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin-CD127+CD161-CRTH2-CD117- (CD161- ILC1s) that can be generated from umbilical cord blood CD34+ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.

DOI: https://doi.org/10.1038/s41467-026-68582-2
bioRxiv. 2026 Jan 20. pii: 2026.01.20.700435. [Epub ahead of print]

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.

Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1α and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

DOI: https://doi.org/10.64898/2026.01.20.700435
Nat Commun. 2026 Feb 05.

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression.

Vincent Cuminetti, Emeline Boet, Marcel Heugel, Joanna Konieczny, Aurora Bernal, Manuel J Gomez, Franco Grimolizzi, Nuria Vilaplana-Lopera, Marc Ferré, Alicia Villatoro, Deo P Pandey, Carlos Torroja, Hagar Taman, Ruth H Paulssen, Thomas Vogl, Caroline A Heckman, Anders Vik, Giovanna Giovinazzo, Nick van Gastel, Paloma García, Fátima Sánchez-Cabo, Jean-Emmanuel Sarry, Lorena Arranz.

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato+ HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

DOI: https://doi.org/10.1038/s41467-026-68906-2
Br J Haematol. 2026 Feb 01.

Selective small molecule targeting of KDM4 as a therapeutic strategy to reduce proliferation of acute myeloid leukaemia.

Laura Monaghan, Roderick P Bunschoten, Joana Bittencourt-Silvestre, Taeju Park, Susan Gannon, Petrisor Alin Pirvan, Alex Hoose, Helen Wheadon, Robert M J Liskamp, Xu Huang, Heather G Jørgensen.

  Acute myeloid leukaemia (AML) is an aggressive disease with poor survival and high relapse rates. Coupled with the complex mutational burden observed, there is an unmet clinical need for more targeted therapies. Epigenetic therapies have shown promise both as monotherapy and in combination strategies and specifically histone lysine demethylase, KDM4A (Lysine demethylase 4), plays a role in the maintenance of AML, with its short hairpin (shRNA) knockdown sufficient to target leukaemia cells while sparing normal haemopoietic cells. In this study, we utilised a novel KDM4 inhibitor based on the structure of IOX-1, the most characterised inhibitor of the 2-oxygenase enzymes to which the KDM4 family belong, to investigate further the role of KDM4A in AML. Our compound induced AML cell death with cell cycle arrest, failure of colony formation and transcriptomic changes in metabolism, transcription control and response to stress. With known roles for KDM4A family members in deoxyribonucleic acid (DNA) damage response repair pathways, inhibition of KDM4A increased accrual of double strand DNA breaks. Hence, we demonstrated KDM4i sensitisation of leukaemia cells to inhibitors of DNA damage pathways such as poly-ADP ribose polymerase (PARP) inhibitor, olaparib, suggesting future clinical evaluation of KDM4A and other key components in DNA damage/response signalling pathways as potential therapeutic vulnerabilities in AML.

Keywords:  AML; KDM4; PARP‐1; epigenetics; histone demethylase

DOI:  https://doi.org/10.1111/bjh.70351
NPJ Precis Oncol. 2026 Jan 30.

Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.

Jiang Wu, Juan Li, Li Xu, Yuanyuan Liu, Li Jiang.

The current study explores the expression, functional significance, and underlying mechanisms of the mitochondrial protein NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4) in glioma cells. TCGA shows that elevated NDUFS4 expression is consistently observed in glioma tissues, correlating with advanced tumor grade and diminished patient survival. Single-cell RNA sequencing further localizes this elevated expression primarily to glioma cells, where NDUFS4 co-expressed genes are integral to cellular respiration and mitochondrial ATP synthesis. These findings were corroborated in patient tissues and various primary and established glioma cell types, confirming consistent NDUFS4 overexpression. Genetic silencing (via shRNA) or CRISPR/Cas9-mediated knockout of NDUFS4 impaired mitochondrial function, evidenced by reduced oxygen consumption rate, inhibited mitochondrial complex I activity and ATP production and increased oxidative stress. NDUFS4 depletion also suppressed glioma cell proliferation, migration, and invasion, while promoting apoptosis. This inhibitory effect is specific to malignant cells, sparing non-cancerous astrocytes. Conversely, NDUFS4 overexpression enhanced mitochondrial activity and promoted aggressive malignant phenotypes in primary and immortalized glioma cells. Further multi-omics integration and experimental investigation established COX5B (cytochrome c oxidase subunit 5B) as an important downstream effector of NDUFS4. shRNA-induced silencing of COX5B replicated the outcomes of NDUFS4 depletion in primary glioma cells, and crucially, restoring COX5B in NDUFS4-silenced glioma cells abrogated the anti-glioma effects. In vivo studies demonstrated that NDUFS4 silencing effectively impeded intracranial growth of patient-derived glioma xenografts by compromising mitochondrial function, downregulating COX5B, inhibiting proliferation and inducing apoptosis. Collectively, these comprehensive data underscore NDUFS4's essential role in glioma progression and position it as a promising therapeutic target for this aggressive malignancy.

DOI: https://doi.org/10.1038/s41698-026-01281-9
J Neuropathol Exp Neurol. 2026 Feb 04. pii: nlag004. [Epub ahead of print]

Gliomas with succinate dehydrogenase deficiency: A case series and brief review of the literature of oncometabolite-driven gliomagenesis.

Madison T Gray, Romain Cayrol, Adriana May, John M Skaugen, Fadi Hayek, Sarah Lapointe, Cynthia E Hawkins, Thomas M Pearce, Drew Pratt, Danica Wiredja, Angus Toland, Daniel F Marker.

  Oncometabolite production plays a key role in the development and progression of isocitrate dehydrogenase-mutant gliomas. The aberrant gain-of-function activity of the mutant isocitrate dehydrogenase protein results in the production of the oncometabolite D-2-hydroxyglutarate, which in turn promotes DNA hypermethylation and gliomagenesis through several mechanisms. Rare gliomas in patients with fumarate hydratase deficiency syndrome share many morphologic and molecular features with isocitrate dehydrogenase-mutant gliomas, with the oncometabolites succinate and 2-succinocysteine similarly thought to promote global DNA hypermethylation. Like isocitrate dehydrogenase and fumarate hydratase, succinate dehydrogenase is also a member of the citric acid cycle that additionally participates in oxidative phosphorylation. While succinate dehydrogenase deficiency has been implicated in familial tumor syndromes, it has not yet been associated with glial neoplasms. Here we report 3 cases of diffuse glioma with succinate dehydrogenase deficiency that show many similarities with isocitrate dehydrogenase-mutant gliomas. We propose that succinate dehydrogenase deficiency with accumulation of the oncometabolite succinate can promote gliomagenesis in a similar manner as seen in isocitrate dehydrogenase-mutant and fumarate hydratase-deficient gliomas, and we discuss the proposed mechanisms that may lead to tumor formation.

Keywords:  glioma; hypermethylation; oncometabolite; succinate dehydrogenase

DOI:  https://doi.org/10.1093/jnen/nlag004
J Med Food. 2026 Feb 04. 1096620X261421080

Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.

Israel Ramirez-Sanchez, Rosa Ordoñez-Razo, Veronica Najera, Guillermo Ceballos, Francisco Villarreal.

  Mitochondrial dysfunction affects skeletal muscle (SkM) function and is critical in the etiology of age-related sarcopenia. The sirtuin 1-PGC1α pathway is a key regulator of mitochondrial mass, structure, and function. However, pathway activity decreases with aging. Cacao flavanols show promise in their ability to activate mitochondrial pathways. We evaluated the capacity of the flavanol (+)-epicatechin (+Epi) to stimulate such a pathway and favorably impact mitochondrial and oxidative stress (OS)-associated endpoints in aged SkM. Using 23-month-old male Sprague-Dawley rats, an 8-week oral administration of +Epi (1 mg/kg/day) was implemented, and results were compared versus vehicle-treated controls. Assessments included the nicotinamide adenine dinucleotide (NAD)/sirtuin 1/PGC1α pathway, acetylated proteins levels, mitochondrial function and biogenesis, as well as OS-related endpoints in SkM. +Epi increased the NAD/NADH ratio, activation of sirtuin 1, the deacetylation of nuclear protein content, including that of PGC1α. Also, +Epi induced increases of TFAM and NRF1 mRNA levels, deacetylation of mitochondrial complex I and V, increases in complex I activity, sirtuin 3, complexes I and V, mitofilin, and TFAM protein levels. SkM citrate synthase activity and ATP content increased with +Epi. OS markers in proteins and lipids were reduced, while buffering systems (superoxide dismutase 2 and catalase protein and activities) increased. In white blood cells, we documented serial reductions in mitochondrial DNA content and citrate synthase activity with aging, which were either fully or partially reversed with +Epi. Results demonstrate that +Epi treatment yields positive effects on mitochondrial biogenesis and function, leading to decreased OS and improved SkM bioenergetics in aged rats.

Keywords:  atrophy; epicatechin; mitochondria

DOI:  https://doi.org/10.1177/1096620X261421080