bims-medica 2025-11-09 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–11–09
29 papers selected by
Brett Chrest, Wake Forest University

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.
Strengths and limitations of Ba/F3 cells in modelling FLT3-driven AML resistance.
Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
IDH2 mutation is associated with favorable outcome among older adults with newly diagnosed acute myeloid leukemia treated with hypomethylating agent-based therapy.
Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.
Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.
Efficacy and safety of ketogenic diets in drug-resistant epilepsy: a systematic review and meta-analysis.
A novel strategy to target metabolic dependencies in acute myeloid leukemia.
Fludarabine metabolism by cytosolic 5'-nucleotidase III and its tissue-specific localization mapping using mass spectrometry imaging.
6-pentadecyl salicylic acid reduces cell proliferation in U373MG glioblastoma cells via glutamine uptake impairment.
Cytochrome c Oxidase Subunit 5A (COX5A) Enhances Gastric Cancer Progression by Augmenting ATP Synthesis and Activating the PI3K/Akt Pathway.
Comparison of the effects of rapamycin and AZD8055 on colon cancer cells through UPLC-MS/MS-based metabolomics.
An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
ESPRESSO: spatiotemporal omics based on organelle phenotyping.
Exploring the potential relationship between serum biomarkers in obese individuals and cancer using FTIR, metabolomics, and lipidomics.
Network meta-analysis of the effects of different dietary patterns on patients with metabolic syndrome.
Inhibition of ATP citrate lyase does not affect muscle mitochondrial activity in apoE-/- mice.
Real-world outcomes of venetoclax and azacitidine in Japanese patients with newly diagnosed acute myeloid leukemia (VENUS study).
Dynamic 13C-MRI of Branched-Chain Amino Acid Metabolism Using Hyperpolarized [1-13C]2-Ketoisocaproate: A Multiband IDEAL Spiral Approach in Rodents and Pigs.
Human Citrate Synthase Post-Translational Modification Mimics and Molecular Dynamic Simulations Demonstrate Attenuation of Acetyl-CoA/CoA Binding.
Association between sociodemographic and clinical factors and utilization of hematopoietic cell transplant in acute myeloid leukemia from 2004 to 2020.
Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy.
The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.
CRISPR-Cas9 in acute myeloid leukaemia: Current state-of-art and future perspectives.
Disruption of acyl-acyl carrier protein (acyl-ACP) synthetase in cyanobacteria impairs lipid remodeling as revealed by acyl-ACP measurements.
Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention.

Science. 2025 Nov 06. eadx9717

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.

Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis.

Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT's enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.

DOI: https://doi.org/10.1126/science.adx9717
Blood. 2025 Nov 05. pii: blood.2025030209. [Epub ahead of print]

Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.

Gentaro Kawano, Riichiro Ikeda, Daisuke Ishihara, Takahiro Shima, Teppei Sakoda, Shunsuke Yamamoto, Yu Kochi, Yuichiro Semba, Sanae Ashitani, Yasuo Mori, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Tomoyoshi Soga, Koichi Akashi, Yoshikane Kikushige.

Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.

DOI: https://doi.org/10.1182/blood.2025030209
Haematologica. 2025 Nov 06.

Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.

Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva.

Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and BH3 profiling. Treatment with DS-1594b and venetoclax exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the NPM1-mutated AML PDX model, DS- 1594b single-agent treatment significantly extended survival. Importantly, compared with DS- 1594b monotherapy, the combination of DS-1594b and venetoclax more profoundly reduced leukemic burden and prolonged mouse survival. Menin inhibition was the primary driver of transcription changes in this model and impacted the expression of antiapoptotic regulators, providing a mechanistic explanation for the synergy observed between these drugs. Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.

DOI: https://doi.org/10.3324/haematol.2024.286833
Bioorg Med Chem Lett. 2025 Nov 01. pii: S0960-894X(25)00365-8. [Epub ahead of print]131 130456

Strengths and limitations of Ba/F3 cells in modelling FLT3-driven AML resistance.

Jingmei Yang, Ran Friedman.

  The Ba/F3 cell line is a widely used model in kinase drug development. Such cells are transformed to depend on a certain kinase for proliferation, and the use of an inhibitor of the kinase thus prevents their growth. We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The cells could be made resistant to the drugs in concentrations that are similar to those in the plasma of patients, but this often required multiple secondary mutations. Several novel inhibitors, designed to be active against FLT3 mutants were tested but could not inhibit the growth of the resistant Ba/F3 cells. Several hitherto unidentified mutations in FLT3 were discovered that lead to drug resistance. These mutations were further studied using computational tools in order to understand how they lead to drug resistance. The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance.

Keywords:  Acute myeloid leukemia; Drug resistance; Kinase inhibitors; Resistance mutations

DOI:  https://doi.org/10.1016/j.bmcl.2025.130456
Nat Commun. 2025 Nov 04. 16(1): 9664

Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.

Berwini B Endaya, Lukáš Kučera, Dan-Diem Thi Le, Jessica B Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J Oliveira, Michael V Berridge, Jiří Neužil.

Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

DOI: https://doi.org/10.1038/s41467-025-65451-2
Haematologica. 2025 Nov 06.

IDH2 mutation is associated with favorable outcome among older adults with newly diagnosed acute myeloid leukemia treated with hypomethylating agent-based therapy.

Fieke W Hoff, Ying Huang, Rina Li Welkie, Ronan T Swords, Elie Traer, Eytan M Stein, Tara L Lin, Maria R Baer, Vu H Duong, William G Blum, Martha L Arellano, Wendy Stock, Olatoyosi Odenike, Joshua F Zeidner, Rebecca L Olin, Catherine C Smith, Gary J Schiller, Emily K Curran, Shivani V Handa, Nyla A Heerema, Timothy Chen, Molly Martycz, Mona Stefanos, Sonja G Marcus, Leonard Rosenberg, Brian J Druker, Ross L Levine, Amy Burd, Ashley O Yocum, Uma M Borate, Alice S Mims, John C Byrd, Yazan F Madanat.

Mutations of isocitrate dehydrogenase (IDH) are recurrent in newly diagnosed (ND) acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH mutations in AML remains controversial. IDH inhibitors generally have a favorable side effect profile, making them an attractive option for older patients. This retrospective analysis aimed to describe the prevalence and prognostic impact of IDH mutations in a large cohort of ND AML patients aged ≥60 years enrolled in the Beat AML clinical trial. A total of 1,023 patients were included. IDH mutations were detected in 28% of the patients, including 9.7% IDH1mut, 18.9% IDH2mut, and 1.0% had a mutation in IDH1 and IDH2. IDH frequently co-occurred with DNMT3A (38%), NPM1 (35%), and SRSF2 (34%). In patients treated with intensive chemotherapy, IDH mutations were not prognostic for overall survival (OS) (p=0.76), while OS was longer for patients with IDH2mut compared to IDHwt in patients treated with hypomethylating agent (HMA)-based therapy (median OS of 18.5 vs 10.2 months, p.

DOI: https://doi.org/10.3324/haematol.2025.288743
Nat Commun. 2025 Nov 03. 16(1): 9667

Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging.

Dan Wu, Bo Tan, Zijie Cheng, Haoqi Li, Huimin Li, Yun Yin, Fenfen Ma, Tao Chen, Xin Dong, Wang Wang, Qingxun Hu.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.

DOI: https://doi.org/10.1038/s41467-025-64652-z
Nat Commun. 2025 Nov 03. 16(1): 9690

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.

Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo, Jung Min Han.

The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-64730-2
Scand J Immunol. 2025 Nov;102(5): e70067

Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.

Zhi Gu, Minghui Zhang, Sheng Xia.

  The metabolic programme of T cells is pivotal in determining their differentiation, development and immune function. T cells undergo distinct metabolic reprogramming at various stages. Effector T cells primarily utilise glycolysis to generate energy quickly, whereas memory T cells depend on fatty acid oxidation (FAO) to sustain long-term survival and enable rapid reactivation. This metabolic differentiation is regulated through metabolic reprogramming by adjusting nutrient utilisation to meet specific demands. Ketone bodies, FAO-derived metabolites, interact with glucose and amino acid metabolism to influence the function and differentiation of T cells and other immune cell subsets. The body's metabolic equilibrium is significantly influenced by dietary patterns. A medically designed dietary intervention that elevates ketone body levels can reshape T-cell metabolism, influencing their differentiation, development and immune functions. This metabolic modulation suggests a potential interplay between nutritional strategies and T-cell immunotherapy applications, especially in the context of tumour immunology. This review explores ketone body metabolism and its impact on T-cell function, offering insights into the clinical use of diet-induced ketosis for T-cell immunotherapy. It also emphasises the potential of metabolic reprogramming to boost T cell performance and improve the efficacy of immunotherapy.

Keywords:  T cell; immunotherapy; ketone body; ketone diet; metabolism

DOI:  https://doi.org/10.1111/sji.70067
World J Pediatr. 2025 Nov 08.

Efficacy and safety of ketogenic diets in drug-resistant epilepsy: a systematic review and meta-analysis.

Alzahra'a Al Matairi, Bara M Hammadeh, Omar Abuhashem, Hamza Anas Marzouk, Husam Aldean H Hussain, Majed Ghlailat, Muaath Ismail Abdullah Alsufi, Osama Aloudat.

   BACKGROUND: Epilepsy affects millions of patients worldwide, and approximately one-third of patients are resistant to antiepileptic drugs. Dietary therapies, such as ketogenic diet (KD), modified Atkins diet (MAD), and low glycemic index treatment, have shown potential in seizure control. This review aims to evaluate the effectiveness and safety of these dietary interventions in reducing seizure frequency and improving related outcomes in individuals with drug-resistant epilepsy.
METHODS: A comprehensive search of PubMed, Scopus, the Cochrane Library, and Web of Science was conducted up to December 2024 and updated in May 2025. Eligible studies were randomized controlled trials and prospective cohort studies evaluating KDs in patients with drug-resistant epilepsy. The primary outcomes included seizure reduction (≥ 50%, ≥ 90%, or complete cessation), whereas the secondary outcomes included cognitive function, quality of life, and adverse events. The risk of bias was assessed via the Cochrane Risk of Bias 2 tool. Meta-analyses were performed via R (version 4.3.2), with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. Fixed- or random-effects models were applied on the basis of heterogeneity levels.
RESULTS: Dietary interventions significantly increased ≥ 50% seizure reduction [odds ratio (OR) = 3.46, 95% CI = 1.83-6.56] compared with standard care, with stronger effects in pediatric patients (OR = 10.93 vs. 2.54 in adults, P = 0.007). MAD outperformed standard care (OR = 4.04), whereas KD did not (OR = 1.83). For a ≥ 90% reduction, KD had greater efficacy (OR = 6.23) than MAD did (OR = 1.98). No significant difference was found for complete seizure resolution (OR = 1.19). Adverse events varied: constipation was most common with MAD (30.97%), whereas KD had higher rates of respiratory infections (42.77%, P < 0.0001 vs. MAD) and diarrhea (13.75% vs. 8.11%, P = 0.0017). Heterogeneity was substantial in most analyses (I2 > 75%).
CONCLUSIONS: KDs and MADs are effective in reducing seizures in patients with drug-resistant epilepsy, especially in children. However, claims of seizure freedom remain uncertain. Further high-quality trials are needed to compare diets and assess long-term safety.

Keywords:  Drug-resistant epilepsy; Ketogenic diet; Low glycemic index therapy; Modified Atkins diet; Seizure freedom; Seizure frequency reduction

DOI:  https://doi.org/10.1007/s12519-025-00981-9
Cell Death Dis. 2025 Nov 04. 16(1): 792

A novel strategy to target metabolic dependencies in acute myeloid leukemia.

Nithya Balasundaram, Hamenth Kumar Palani, Arvind Venkatraman, Yolanda Augustin, Shruthi Pichandi, Clement Regnault, Majeela Solomon, Abirami Rajasekaran, Mohammed Yasar, Swathy Palani Kumar, Reeshma Nair Radhakrishnan, Anu Korula, Uday Prakash Kulkarni, Eunice Sindhuvi Edison, Poonkuzhali Balasubramanian, Biju George, Aby Abraham, Sanjeev Krishna, Vikram Mathews.

Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.

DOI: https://doi.org/10.1038/s41419-025-08129-3
Drug Metab Dispos. 2025 Oct 09. pii: S0090-9556(25)09487-5. [Epub ahead of print]53(11): 100178

Fludarabine metabolism by cytosolic 5'-nucleotidase III and its tissue-specific localization mapping using mass spectrometry imaging.

Maisa Khan, Nav Raj Phulara, Herana Kamal Seneviratne.

  Nucleotidases are enzymes that play vital roles in nucleotide pool balance and purine and pyrimidine metabolism across various tissues. Two major forms of nucleotidases, 5'-nucleotidases (5'-NTs) and nucleoside triphosphate diphosphohydrolases, dephosphorylate nucleoside monophosphates and triphosphates, respectively. Recently, our laboratory reported the dephosphorylation action of these nucleotidases toward the metabolites of clinically used nucleoside analog drugs, including gemcitabine, emtricitabine, tenofovir, and acyclovir. Here, we extended investigating the role of 5'-NTs in disposition of fludarabine, a drug used to treat B-cell chronic lymphocytic leukemia. In vitro incubations carried out using 5 human recombinant 5'-NTs, including cytosolic 5'-nucleotidase 1A (NT5C1A), NT5C2, NT5C3, NT5C, and mitochondrial 5' (3')-deoxyribonucleotidase revealed that NT5C3 catalyzed the dephosphorylation of fludarabine. Although nucleotidases have critical roles in metabolism of endogenous nucleotides and xenobiotics, their spatial localization in tissues is not fully elucidated yet. In the present work, we employed matrix-assisted laser desorption/ionization mass spectrometry imaging to ascertain localizations of tryptic peptides corresponding to major nucleotidases in mouse kidney, colon, and spleen tissues. First, in silico trypsin digestions were performed to determine the trypsin digestion patterns of the above proteins. Then, recombinant nucleotidases were used to characterize tryptic peptides of major nucleotidases. Following this, matrix-assisted laser desorption/ionization mass spectrometry imaging analyses were carried out to localize tryptic peptides corresponding to major nucleotidases in mouse colon, kidney, and spleen tissues. From tissue imaging experiments, we observed localizations of NT5C3 peptides in distinct regions such as the kidney cortex and colonic mucosa. SIGNIFICANCE STATEMENT: Nucleotidases, including cytosolic 5'-nucleotidase (NT5C) 3, have important roles in the endogenous nucleotide metabolism. Additionally, they may catalyze the dephosphorylation reactions of nucleoside analog drugs and their metabolites due to the structural similarities. Using in vitro incubations and enzyme kinetics, we demonstrate the involvement of NT5C3 in the dephosphorylation of an important antineoplastic agent, fludarabine. Furthermore, we employed mass spectrometry imaging to visualize peptides corresponding to NT5C3 and other major nucleotidases in the kidney cortex and colonic mucosa.

Keywords:  Drug metabolism; Fludarabine; Matrix-assisted laser desorption/ionization mass spectrometry imaging; Nucleotidases

DOI:  https://doi.org/10.1016/j.dmd.2025.100178
Toxicol Mech Methods. 2025 Nov 06. 1-9

6-pentadecyl salicylic acid reduces cell proliferation in U373MG glioblastoma cells via glutamine uptake impairment.

Laura I Méndez, Andrea Ocharán-Mercado, Luisa C Hernández-Kelly, Jaqueline Loaeza-Loaeza, Daniel Hernández-Sotelo, Francisco Castelán, Libia Vega, Marie-Paule Felder-Schmittbuhl, Arturo Ortega.

  Glioblastoma cells exhibit a pronounced dependence on glutamine uptake, primarily via the alanine‑serine‑cysteine transporter 2, since its deletion prevents glioma growth, making this transporter an attractive therapeutic target. This study aimed to evaluate 6‑pentadecyl salicylic acid, a natural antineoplastic and immunomodulatory compound, for its ability to impair alanine‑serine‑cysteine transporter 2‑mediated glutamine transport and by these means reduce glioblastoma cells viability. Human U373MG glioma cells and primary chick cerebellar Bergmann glia (non‑malignant control) were exposed to increasing concentrations of 6SA for 24 h. Viability, measured by the MTT assay, declined in a dose‑dependent manner in U373MG cells while Bergmann glia remained largely unaffected (p < 0.001). L-[³H]-glutamine uptake assays revealed that 100 µM 6SA functioned as a potent inhibitor, increasing the Michaelis constant (KM) more than four-fold (from 7.11 mM to 31.79 mM). This indicates a mixed-type or competitive inhibition mechanism that dramatically reduces the transporter's apparent affinity for glutamine and prevents saturation within the tested substrate range. Additionally, quantitative PCR showed a dose‑dependent down‑regulation of ASCT2 mRNA, suggesting post‑transcriptional control. Blind docking of 6SA onto the cryo‑EM ASCT2 structure identified nine peripheral cavities that could serve as allosteric sites, however, these predictions are computational and require experimental validation; binding to these sites would stabilize a low‑affinity transporter conformation, consistent with the kinetic data. Collectively, 6‑pentadecyl salicylic acid selectively impairs glutamine transport and viability in glioblastoma cells while sparing normal glial cells, supporting its potential as a lead compound for alanine‑serine‑cysteine transporter 2 ‑targeted glioma therapy.

Keywords:  6-pentadecyl salicylic acid glutamine; U373MG cells; cell proliferation; glioblastoma; glutamine transporters

DOI:  https://doi.org/10.1080/15376516.2025.2579574
J Cell Mol Med. 2025 Nov;29(21): e70922

Cytochrome c Oxidase Subunit 5A (COX5A) Enhances Gastric Cancer Progression by Augmenting ATP Synthesis and Activating the PI3K/Akt Pathway.

Dongyan Li, Limin Zhou.

  Gastric cancer (GC) is a lethal malignancy characterised by poor prognosis. In this study, we identify cytochrome c oxidase subunit 5A (COX5A) as a key metabolic driver and prognostic biomarker in GC. COX5A was upregulated in tumours and correlated with poor survival. Mechanistically, COX5A enhanced mitochondrial oxidative phosphorylation to elevate ATP production, activating PI3K/Akt signalling to drive proliferation, migration, and invasion. These effects were reversed by PI3K/Akt inhibitors. JC-1 assays revealed COX5A-mediated mitochondrial membrane potential elevation, indicating amplified bioenergetic output. In vivo, COX5A silencing suppressed xenograft tumour growth. Our results demonstrate COX5A orchestrates metabolic reprogramming and PI3K/Akt-mediated progression in GC, positioning it as both a prognostic indicator and therapeutic target.

Keywords:  ATP synthesis; COX5A; PI3K/Akt pathway; gastric cancer; mitochondrial function

DOI:  https://doi.org/10.1111/jcmm.70922
J Pharm Biomed Anal. 2025 Nov 01. pii: S0731-7085(25)00567-9. [Epub ahead of print]268 117226

Comparison of the effects of rapamycin and AZD8055 on colon cancer cells through UPLC-MS/MS-based metabolomics.

Kai Fan, Yueyuan Wang, Bo Lv, Xinyun Zhang, Chen Feng, Jianxin Yang, Jie Pan, Yunli Yu.

  mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel AZD8055 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that AZD8055 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with AZD8055 and rapamycin. Through variable importance in the projection (VIP) value screening, we pinpointed crucial metabolites contributing to these distinctions. The results indicate that both inhibitors suppress tumor cell growth by downregulating amino acid metabolism, inhibiting glucose metabolism, and enhancing oxidative stress, with AZD8055 exhibiting stronger anti-proliferative efficacy. Specifically, the AZD8055 group showed significantly reduced levels of glucose and lactate, suggesting a more potent suppression of aerobic oxidation and glycolysis. Concurrently, a marked increase in taurine levels was observed in the AZD8055 group, further enhancing its antioxidant and anti-tumor effects. Although both compounds similarly inhibited branched-chain amino acid (BCAA) metabolism, comprehensive metabolic analysis revealed that AZD8055 has greater potential in modulating tumor metabolic pathways, thereby providing new theoretical support for the translational development of mTORC1/2 dual inhibitors.

Keywords:  AZD8055; Colon cancer; MTORC1/2; Metabolism; Rapamycin

DOI:  https://doi.org/10.1016/j.jpba.2025.117226
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894

An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.

Zachary L Sebo, Navdeep S Chandel.

Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.

DOI: https://doi.org/10.1016/j.molcel.2025.10.017
Nat Methods. 2025 Nov 03.

ESPRESSO: spatiotemporal omics based on organelle phenotyping.

Lorenzo Scipioni, Giulia Tedeschi, Mariana X Navarro, Yunlong Y Jia, Songning Zhu, Lila P Halbers, Melody Di Bona, Scott X Atwood, Jennifer A Prescher, Enrico Gratton, Michelle A Digman.

Omics technologies such as genomics, transcriptomics, proteomics and metabolomics methods, have been instrumental in improving our understanding of complex biological systems by providing high-dimensional phenotypes of cell populations and single cells. Despite fast-paced advancements, these methods are limited in their ability to include a temporal dimension. Here, we introduce ESPRESSO (Environmental Sensor Phenotyping RElayed by Subcellular Structures and Organelles), a technique that provides single-cell, high-dimensional phenotyping resolved in space and time. ESPRESSO combines fluorescent labeling, advanced microscopy and image and data analysis methods to extract morphological and functional information from organelles at the single-cell level. We validate ESPRESSO's methodology and its application across numerous cellular systems for the analysis of cell type, stress response, differentiation and immune cell polarization. We show that ESPRESSO can correlate phenotype changes with gene expression, and demonstrate its applicability to 3D cultures, offering a path to improved spatially and temporally resolved biological exploration of cellular states.

DOI: https://doi.org/10.1038/s41592-025-02863-4
Metabolomics. 2025 Nov 03. 21(6): 158

Exploring the potential relationship between serum biomarkers in obese individuals and cancer using FTIR, metabolomics, and lipidomics.

Maria Eduarda Marques, Natália Ferreira Silva, Fernanda Naves Araújo do Prado Mascarenhas, Tatiana Carla Tomiosso, Robson José de Oliveira Júnior, Ricardo Rodrigues, Hebreia Oliveira Almeida-Souza, Mário Machado Martins, Luciana Machado Bastos, Arlene Bispo Dos Santos Nossol, Tiara da Costa Silva, Camila Moreira de Andrade, Marco Fidel Guevara-Vega, Robinson Sabino-Silva, Carlos Ueira-Vieira, Renata Graciele Zanon.

   INTRODUCTION: Robust evidence endorsed by the International Agency for Research on Cancer demonstrates that excess body fat represents a risk for the development of at least 13 types of cancer.
OBJECTIVE: We investigated the serum of individuals with obesity who had no history of cancer (either personal or familial) to identify biomarkers.
METHODS: 45 individuals were included in this study; they did not show significant differences regarding age, sex, or physical activity. A quality-of-life questionnaire was administered to all participants, revealing that the obese group self-reported difficulties in functional capacity and a greater association with comorbidities, notably hypertension. FTIR, metabolomic, and lipidomic analyses were performed to identify spectral peaks, metabolic, and lipids differentiating between the NO (non-obese) and OB (obese) groups.
RESULTS: The identified peaks are predominantly associated with profiles of lipids, carbohydrates, and nitrogenous compounds. A total of six metabolites and lipids were identified at different levels in the serum of the OB group that have a direct relationship with the development or metabolism of cancer cells (three metabolites and three lipids). Among these, some suggest a reduced likelihood of cancer development, while others indicate an increased potential for cancer development. In this context, we can highlight two substances: the metabolite 4-Hydroxyphenylglyoxylate, which is reduced in the serum of individuals with obesity, and the lipid Glycidyl palmitate, which is elevated in individuals with obesity.
CONCLUSION: 4-Hydroxyphenylglyoxylate and Glycidyl palmitate can be used as biomarkers for cancer and obesity correlation. New experiments manipulating these substances may contribute to a better understanding of their interactions with cancer cells.

Keywords:  Cancer; Metabolomics; Neoplasia; Obesity; Overweight

DOI:  https://doi.org/10.1007/s11306-025-02351-y
Front Nutr. 2025 ;12 1634545

Network meta-analysis of the effects of different dietary patterns on patients with metabolic syndrome.

Jie Lv, Shiyu Jiao, Wenjing Li, Shuo Ding, Li Ma, Qian Zhang.

   Background: Dietary patterns play an important role in the management of metabolic syndrome (MetS). Previous meta-analyses have shown that the ketogenic diet, the Dietary Approaches to Stop Hypertension (DASH) diet, the vegetarian diet, the Mediterranean diet, the low-fat diet, and the low-carbohydrate diet are beneficial for patients with MetS, but there is still a lack of direct comparison of the intervention effects of the above six dietary patterns.
Objective: This study aimed to explore the intervention efficacy of different dietary patterns on MetS and to evaluate and compare the corresponding effects.
Methods: A comprehensive search was carried out in electronic databases such as Embase, Cochrane Library, PubMed, Web of Science, Scopus, CNKI, Wanfang, VIP, and CBM. The search covered studies published from the establishment of the databases up to 1 April 2025, with a focus on dietary patterns that can improve metabolic syndrome. A network meta-analysis was carried out using Stata 16.0 software.
Results: Eventually, 26 randomized controlled trials were included, involving 2,255 patients. The results of the network meta-analysis showed that the DASH diet [MD = -5.72, 95% CI (-9.74, -1.71)] and the vegan diet [MD = -12.00, 95% CI (-18.96, -5.04)] were more effective in reducing the waist circumference of patients with MetS than the control diet group. In terms of lowering blood pressure, the DASH diet [MD = -5.99, 95% CI (-10.32, -1.65)] and the ketogenic diet [MD = -11.00, 95% CI (-17.56, -4.44)] were more effective in reducing systolic blood pressure in patients with MetS than the control diet group. The ketogenic diet [MD = -9.40, 95% CI (-13.98, -4.82)] was more effective in reducing diastolic blood pressure in patients with MetS than the control diet group (p < 0.05). According to the ranking results, a vegan diet is the best choice in terms of reducing waist circumference and increasing high-density lipoprotein cholesterol levels. The ketogenic diet is highly effective in lowering blood pressure and triglyceride levels. The Mediterranean diet is highly effective in regulating fasting blood glucose.
Conclusion: The current evidence indicates that the vegan diet, the ketogenic diet, and the Mediterranean diet might have more pronounced effects in ameliorating MetS. Further high-quality research is needed to validate these findings.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD420251052075).

Keywords:  dietary interventions; dietary patterns; metabolic syndrome; network meta-analysis; randomized controlled trial

DOI:  https://doi.org/10.3389/fnut.2025.1634545
Biomed Pharmacother. 2025 Nov 04. pii: S0753-3322(25)00920-5. [Epub ahead of print]193 118726

Inhibition of ATP citrate lyase does not affect muscle mitochondrial activity in apoE-/- mice.

Chiara Macchi, Isabella Fichtner, Tasnim Mohamed, Elsa Franchi, Alessandra Stefania Rizzuto, Chiara Pavanello, Jurgen Gindlhuber, Simone Nerini, Cesare R Sirtori, Elena Osto, Stefano Carugo, Marco Busnelli, Giulia Chiesa, Valerio Magnaghi, Alberto Corsini, Massimiliano Ruscica.

   INTRODUCTION: Lipid-lowering therapy is a cornerstone in preventing coronary disease. Bempedoic acid is recommended in patients who are unable to take statin therapy to achieve the low-density lipoprotein cholesterol goal. Based on the hypothesis that statins impact skeletal mitochondrial activity, this study aimed to evaluate the effect of bempedoic acid on this aspect in apoE-/- mice fed a high-fat high-cholesterol (HFHC) diet and compare it to the results obtained using atorvastatin.
METHODS: Female apoE-/- mice. The following techniques were used: En face analysis of aorta, mitostress analysis of skeletal muscles mitochondria, and transmission electron microscopy analysis of muscle fibres.
RESULTS: After 12 weeks, body weight, food intake, glycaemic profile, and liver enzymes were unaffected by bempedoic acid. However, the treatment significantly reduced the plaque in thoracic and abdominal segments, as well as the necrotic core area. Mitochondrial functionality of skeletal muscles (tibialis anterior, extensor digitorum longus, soleus, gastrocnemius, quadriceps, biceps brachii) in mice receiving bempedoic acid was not reduced compared to mice fed only HFHC diet, whereas mice receiving HFHC plus atorvastatin showed a significant reduction in basal and maximal mitochondrial respiration. Cumulative energy expenditure and oxygen consumption were reduced in the atorvastatin group compared to control and bempedoic acid groups. Transmission electron microscopy analysis of muscle fibres of tibialis anterior showed that bempedoic acid did not affect the morphology and distribution of mitochondria. The same analysis in mice fed HFHC plus atorvastatin showed fragmented mitochondria.
CONCLUSIONS: In apoE-/- mice, bempedoic acid positively impacts plaque burden while preventing skeletal muscle mitochondrial dysfunction.

Keywords:  Atherosclerosis; Bempedoic acid; Mitochondrial activity; Skeletal muscles; Statins

DOI:  https://doi.org/10.1016/j.biopha.2025.118726
Int J Hematol. 2025 Nov 07.

Real-world outcomes of venetoclax and azacitidine in Japanese patients with newly diagnosed acute myeloid leukemia (VENUS study).

Ryota Imanaka, Hiroki Numata, Yuna Katsuoka, Nobuhiko Uoshima, Satoru Hara, Jun Ando, Shuichi Ota, Goichi Yoshimoto, Akihito Matsuoka, Tetsuo Morita, Atsuko Tsutsui, Mizuha Kosugi-Kanaya, Tatsunori Goto.

  Venetoclax (VEN) with azacitidine (AZA) is the standard treatment for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, real-world evidence on dosing, scheduling, and outcomes is lacking, particularly for patients with prior myelodysplastic syndrome (MDS) or AZA treatment, who have been excluded from clinical trials. This was a multicenter retrospective study of VEN + AZA in 120 patients newly diagnosed with AML between June 2021 and September 2022. The cohort had a median age of 77 years, 52% had secondary AML, 74% had previously been diagnosed with MDS, and 39% had previously received AZA. During cycle 1, half of the patients received 400 mg of VEN for a median of 27 days, with a median holding period of 12 days. With a median follow-up of 13.6 months, the rate of complete remission (CR) or CR with incomplete blood count recovery was 56.7% in VEN + AZA-treated patients in the overall cohort and 56.5% in patients with prior MDS. Median overall survival was 14.8 months for the overall cohort and 15.4 months for those with prior MDS. The real-world outcomes were comparable to those of clinical trials.

Keywords:  Acute myeloid leukemia; Azacitidine; Myelodysplasia; Venetoclax

DOI:  https://doi.org/10.1007/s12185-025-04093-y
Magn Reson Med. 2025 Nov 06.

Dynamic 13C-MRI of Branched-Chain Amino Acid Metabolism Using Hyperpolarized [1-13C]2-Ketoisocaproate: A Multiband IDEAL Spiral Approach in Rodents and Pigs.

Ingeborg S Skre, Ditte B Christensen, Magnus Karlsson, Jan H Ardenkjær-Larsen, Rie B Olin, Mathilde H Lerche.

   PURPOSE: To develop and validate a dynamic 13C-MRI acquisition strategy for imaging branched-chain amino acid (BCAA) metabolism catalyzed by branched-chain aminotransferase (BCAT) using hyperpolarized [1-13C]2-ketoisocaproate (KIC), and to assess its scalability to a large-animal model.
METHODS: A multiband spectral-spatial excitation was combined with IDEAL spiral imaging at 3 T to capture conversion of KIC to [1-13C]leucine. Hyperpolarized KIC was produced by dissolution dynamic nuclear polarization (dDNP). The method was validated in phantoms mimicking in vivo conditions and applied in mouse brains, where BCAT activity is well characterized. To assess translational feasibility, the protocol was adapted for pig kidneys, a well-perfused organ with renal physiology and BCAT expression similar to humans.
RESULTS: Phantom studies confirmed spectral separation and accurate spatial localization. In mice, the multiband IDEAL spiral sequence generated metabolic maps comparable to chemical-shift imaging but with higher SNR. Dynamic imaging at 1 s temporal resolution captured reproducible KIC-to-leucine conversion across six animals. In pigs, 2 s-resolution imaging revealed KIC uptake in renal vasculature and cortex followed by cortical leucine accumulation and efflux into the vena cava, reflecting localized metabolism and transport.
CONCLUSION: The presented 13C-MRI strategy enables efficient spectral separation and high-temporal-resolution imaging of KIC metabolism in rodents and pigs, establishing a translatable framework for noninvasive studies of BCAA metabolism.

Keywords:  13C; 2‐ketoisocaproate; IDEAL; hyperpolarization; metabolic imaging; multiecho spiral imaging

DOI:  https://doi.org/10.1002/mrm.70167
Proteins. 2025 Nov 03.

Human Citrate Synthase Post-Translational Modification Mimics and Molecular Dynamic Simulations Demonstrate Attenuation of Acetyl-CoA/CoA Binding.

Noah Shackelford, Zach Zavodny, Nathan Fancher, Michael A Moxley.

  Human citrate synthase (hCS) is a mitochondrial enzyme that catalyzes the aldol condensation of acetyl coenzyme A (AcCoA) to oxaloacetate to form citrate in the TCA cycle. CS activity is important for aerobic exercise performance and basic metabolic function as a housekeeping enzyme. It has been shown through several mass spectrometry-based physiological studies that CS is post-translationally modified (PTM) on numerous residues via acetylation, phosphorylation, and methylation reactions. Few follow-up studies have been reported on the impact of PTMs on CS activity. Thus, we kinetically characterized several hCS PTM mimics near and distant from the active site by site-directed mutagenesis coupled with steady-state kinetics. Most modifications had a negative impact on AcCoA kcat/Km but to a much lesser extent on oxaloacetate kcat/Km. Most notably, the K393 acetylation mimic, K393Q displays an increase in Km for AcCoA relative to WT by about 30-fold, with no significant change in kcat. To complement our kinetic analyses, we performed molecular dynamics simulations on 26 PTM and mutant CS-substrate complexes, providing a combined kinetic and MD simulation approach. Among the MD results, CS K393AcK showed the greatest reduction in AcCoA/CoA binding.

Keywords:  enzyme kinetics; molecular dynamics; post‐translational modifications

DOI:  https://doi.org/10.1002/prot.70082
Cancer Epidemiol. 2025 Nov 01. pii: S1877-7821(25)00212-7. [Epub ahead of print]99 102952

Association between sociodemographic and clinical factors and utilization of hematopoietic cell transplant in acute myeloid leukemia from 2004 to 2020.

Utsav Joshi, Aditya Ravindra, Bradley Loeffler, Uttam Bhetuwal, Shishir Acharya, Chengu Niu, Avantika Pyakuryal, Vijaya Raj Bhatt, Prajwal Dhakal.

   INTRODUCTION: This study investigates the influence of sociodemographic and clinical factors on the utilization of hematopoietic cell transplant (HCT) in patients with acute myeloid leukemia (AML) between 2004 and 2020.
METHODS: Patients identified from the National Cancer Database were grouped into two cohorts (2004-2010 and 2011-2019) to assess HCT trends. An additional analysis was conducted for 2020 to characterize HCT use after the onset of the COVID-19 pandemic. Logistic regression and multivariable analysis were used to estimate the influence of patient characteristics on the odds of receiving HCT.
RESULTS: Among 67,895 AML patients, 6968 (10.3 %) underwent HCT, with usage rising from 7.2 % in 2004-13.4 % in 2019. There was a notable increase in HCT utilization among patients > 70 years (0.4 % in 2004-2010-2.5 % in 2011-2019), Black patients (4.6-7.7 %), those with public insurance (3.2-6.2 %), and individuals with higher Charlson Comorbidity Index (CCI 1: 5.3-8.2 %; CCI 2-3: 1.9-4.8 %). Younger patients exhibited a higher likelihood of receiving HCT, with usage declining significantly with age and increasing CCI. Key factors such as race, education, income, insurance status, and AML subtype were significantly associated with HCT utilization (p < 0.01). Remarkably, HCT utilization for AML remained stable at 13.1 % in 2020 amid COVID-19 pandemic, comparable to 2019.
CONCLUSION: The rate of HCT utilization has continued to increase over time, with notable positive trends across various demographic groups. Despite this, substantial barriers related to sociodemographic and clinical factors hinder equitable treatment access, highlighting urgent need to address these inequities to enhance patient outcomes.

Keywords:  Acute myeloid leukemia; Disparity; Hematopoietic cell transplant; Social driver; Survival outcome

DOI:  https://doi.org/10.1016/j.canep.2025.102952
Blood. 2025 Nov 05. pii: blood.2024027948. [Epub ahead of print]

Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy.

Sven Turkalj, Felix A Radtke, Bilyana Stoilova, Rabea Mecklenbrauck, Angus J Groom, Niels Asger Jakobsen, Curtis A Lachowiez, Marlen Metzner, Batchimeg Usukhbayar, Mirian Angulo Salazar, Zhihong Zeng, Sanam Loghavi, Jennifer Marvin-Peek, Verena Körber, Farhad Ravandi, Ghayas C Issa, Tapan M Kadia, Vasiliki Symeonidou, Anne P de Groot, Hagop M Kantarjian, Koichi Takahashi, Marina Konopleva, Courtney D DiNardo, Paresh Vyas.

Acquired resistance to targeted, non-intensive therapies is common in myeloid malignancies. However, the kinetics of selection, the hematopoietic cell compartments where selection occurs, and the molecular mechanisms underlying selection remain open questions. To address this, we studied the kinetics of clonal and transcriptional responses to ivosidenib + venetoclax ± azacitidine combination therapy across hematopoiesis in 8 patients with IDH1-mutant myeloid malignancy. All 8 patients initially responded to treatment but 6 relapsed while 2 remained in sustained remission for >4 years. We performed combined high-sensitivity single-cell (sc) genotyping and scRNA-seq in index-sorted sequential patient samples. In all patients, clonal selection occurred rapidly, within 1-3 treatment cycles. Clonal selection preceded treatment failure by months to years. Relapse was associated with expansion of either clones harboring newly-detected myeloid driver mutations or pre-existing minor clones that underwent differentiation delay upon treatment exposure. In both cases, clonal selection occurred within immature cell populations previously shown to contain leukemic stem cell (LSC) potential. Different genetic alterations within relapse-associated clones converged onto common upregulated transcriptional programs of stemness, branched-chain amino acid catabolism, and genes sensitive to menin inhibition. Importantly, this relapse-associated transcriptional signature was selected within 3 cycles of therapy. In contrast, in both patients remaining in remission, leukemic clones were rapidly eradicated and replaced by clonal and wild-type hematopoiesis. Overall, in patients treated with ivosidenib combination therapy, rapid clonal selection occurs within the first treatment cycles. In those patients destined to relapse, genetically heterogeneous resistant clones are characterized by common transcriptional programs.

DOI: https://doi.org/10.1182/blood.2024027948
J Physiol. 2025 Nov 02.

The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.

Shahrzad Khajehzadehshoushtar, Luca J Delfinis, Fasih A Rahman, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Zhu-Xu Zhang, Jeremy A Simpson, Joe Quadrilatero, Jim Petrik, Christopher G R Perry.

  The degree to which mitochondrial-linked programmed cell death pathways contribute to skeletal muscle atrophy during cancer remains unknown. Here we combined a novel and robust mouse model of metastatic ovarian cancer with chronic administration of the mitochondrial-targeted antioxidant SkQ1 to determine the time-dependent and muscle-specific relationships of mitochondrial-linked apoptotic and necroptotic signalling to the development of muscle atrophy in the type IIB-rich gastrocnemius. Early-stage ovarian cancer reduced type IIB fibre cross-sectional area in the gastrocnemius but did not alter mitochondrial H2O2 emission despite increased activities of mitochondrial-linked caspase-9 and -3 regulators of apoptosis. During late-stage ovarian cancer sustained atrophy was associated with increased mitochondrial H2O2 emission potential in vitro, a greater probability of calcium-triggered mitochondrial permeability transition and increases in downstream caspase-9 and -3 activities. SkQ1 attenuated mitochondrial H2O2 emission and caspase-9 and -3 activities in late-stage ovarian cancer but did not prevent atrophy. Necroptosis markers were heterogeneous across time with total RIPK1 increasing during early-stage cancer, which reverted to normal levels by late stages, whereas phosphorylated RIPK3 decreased below control levels. These discoveries indicate that preventing increases in mitochondrial-linked apoptotic caspase-9 and -3 activities during late-stage ovarian cancer with SkQ1 does not prevent atrophy of type II B fibres. Furthermore necroptotic markers are inconclusive during cancer in this muscle type but are not modified by SkQ1. These results do not support a causal relationship between mitochondrial H2O2-linked apoptotic or necroptotic signalling and atrophy in type IIB fibres during ovarian cancer but do not rule out potential relationships in other muscle types. KEY POINTS: Cancer increases mitochondrial reactive oxygen species (ROS) in skeletal muscle during atrophy, but the role of ROS in regulating cell death remains unknown. We show that attenuating gastrocnemius mitochondrial ROS with the mitochondrial-targeted antioxidant SkQ1 prevented mitochondrial-linked pro-apoptotic caspase 9- and -3 activities but did not affect markers of necroptosis in a mouse model of ovarian cancer. Reductions in gastrocnemius muscle fibre cross-sectional areas and the wet weights of several muscles were not prevented by SkQ1. These findings demonstrate that mitochondrial ROS regulate apoptotic caspases but not necroptotic proteins, and neither pathway is linked to gastrocnemius atrophy in mice with ovarian cancer. The degree to which mitochondrial ROS-linked cell death pathways regulate muscle mass in other muscle types and cancer models requires further investigation.

Keywords:  apoptosis; cachexia; mitochondria; necroptosis; ovarian cancer; skeletal muscle

DOI:  https://doi.org/10.1113/JP287912
Curr Opin Pharmacol. 2025 Oct 16. pii: S1471-4892(25)00078-5. [Epub ahead of print]85 102582

CRISPR-Cas9 in acute myeloid leukaemia: Current state-of-art and future perspectives.

Federico Zingarelli, Jacopo Nanni, Gianluca Cristiano, Letizia Zannoni, Antonio Curti.

CRISPR-Cas9 gene editing technology has gained attention as a new, reliable and manageable tool for the treatment of previously incurable monogenic diseases. Besides exciting results in this setting, ethical, safety and crucial technical issues have not been fully clarified. More importantly, the role of this potent editing tool in the context of a genetically complex and heterogeneous hematologic malignancy such as acute myeloid leukemia (AML) has not yet been defined to date. In this review we aim to summarize and exploring the ultimate CRISPR-cas9 based strategies for diagnosis, risk stratification and treatment in the context of AML.

DOI: https://doi.org/10.1016/j.coph.2025.102582
Metab Eng. 2025 Nov 05. pii: S1096-7176(25)00171-5. [Epub ahead of print]

Disruption of acyl-acyl carrier protein (acyl-ACP) synthetase in cyanobacteria impairs lipid remodeling as revealed by acyl-ACP measurements.

Juthamas Jaroensuk, Joshua P Abraham, Baltazar E Zuniga, Hawkins S Shepard, Michael Wei, Russell Williams, Stewart A Morley, Maneesh Lingwan, Jiahong Zhou, Michael A Jindra, Poonam Jyoti, Bo Wang, Jody C May, John A McLean, Jamey D Young, Brian F Pfleger, Doug K Allen.

  Free fatty acid (FFA) production in bacteria is a key target for metabolic engineering. The knockout of the acyl-ACP synthetase (AAS) prevents reincorporation of FFA into the fatty acid biosynthetic cycle and is widely used to enhance their secretion. However, the role of AAS in membrane lipid remodeling under environmental stress, such as altered temperature, remains poorly understood. In cyanobacteria, temperature shifts are known to affect fatty acid desaturation and membrane fluidity, yet it is unclear whether AAS contributes to these adaptive responses through re-esterification of membrane-released acyl chains. We elucidated unique aspects of fatty acid metabolism in response to temperature changes in biotechnologically relevant microbes with the development of an efficient method for quantifying acyl-ACP intermediates using anion exchange chromatography (AEX). In Escherichia coli, which performs desaturation during fatty acid biosynthesis, we detected saturated and unsaturated acyl-ACPs that confirm biosynthetic pathway operation. In the cyanobacteria, Picosynechococcus sp. PCC 7002 and the Δaas strain, changes between two temperatures were interpreted with support from proteomic and lipidomic analyses and indicated that the AAS is tied to membrane lipid remodeling. Further, polyunsaturated acyl-ACPs were detected in the Δaas strain, which was unexpected because fatty acid synthesis does not produce polyunsaturates in cyanobacteria, suggesting the presence of alternative acyl-activating enzymes or unknown acyl-ACP desaturases. This study highlights the possible link between acyl chain recycling and lipid remodeling in cyanobacteria and demonstrates the utility of AEX-based acyl-ACP profiling in dissecting fatty acid metabolism.

Keywords:  Fatty acid synthesis; acyl-ACP synthetase; biofuel; cyanobacteria; lipid remodeling; systems biology

DOI:  https://doi.org/10.1016/j.ymben.2025.11.004
Sci Rep. 2025 Nov 07. 15(1): 39093

Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention.

Ville M Koistinen, Suvi Manninen, Marjo Tuomainen, Kirsikka Aittola, Elina Järvelä-Reijonen, Tanja Tilles-Tirkkonen, Reija Männikkö, Niina Lintu, Leila Karhunen, Marjukka Kolehmainen, Santtu Mikkonen, Marko Lehtonen, Janne Martikainen, Kaisa Poutanen, Ursula Schwab, Pilvikki Absetz, Jaana Lindström, Timo A Lakka, Kati Hanhineva, Jussi Pihlajamäki.

  Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal-Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.

Keywords:  Acylcarnitines; Amino acids; Fatty acid amides; Impaired glucose metabolism; Metabolomics; Personalized treatment; Phospholipids

DOI:  https://doi.org/10.1038/s41598-025-25749-z