bims-medica 2025-08-31 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–08–31
24 papers selected by
Brett Chrest, Wake Forest University

Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.
Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
Evolutionary diversity of muscle OXPHOS efficiency in vitro across ectothermic vertebrates.
GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.
ACAA1 knockout increases the survival rate of KPC mice by activating autophagy.
Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes.
Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
Ketogenic diet ameliorates MASLD via balancing mitochondrial dynamics and improving mitochondrial dysfunction.
Quantitative imaging of lipid transport in mammalian cells.
Single-cell multi-omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC-unique features.
Mechanical confinement governs phenotypic plasticity in melanoma.
Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells.
Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.
Real-world generalizability of clinical trial cytomolecular risk in pediatric acute myeloid leukemia: a report from the REAL-AML cohort.
Carnitine Shuttle and Ferroptosis in Cancer.
Targeting of Mutant Isocitrate Dehydrogenase in Glioma: A Systematic Review.
Succinylation - encoded metabolic codes: cracking the molecular logic of cellular adaptation.
Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast.
Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain.
Mitochondrial activity tunes nociceptor resilience to excitotoxicity.
Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.
Investigation and Distinction of Energy Metabolism in Proliferating Hepatocytes and Hepatocellular Carcinoma Cells.
Image-based drug screening combined with molecular profiling identifies signatures and drivers of therapy resistance in pediatric AML.

Cancer Metab. 2025 Aug 20. 13(1): 38

Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.

Xu Han, Laura C Kim, Nicholas P Lesner, Xuanyan Cai, Tran Ngoc Van Le, M Celeste Simon.

BACKGROUND: Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.
METHODS: We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.
RESULTS: CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.
CONCLUSION: Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC.

DOI: https://doi.org/10.1186/s40170-025-00389-z
Nat Commun. 2025 Aug 26. 16(1): 7934

Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.

Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.

Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.

DOI: https://doi.org/10.1038/s41467-025-63243-2
Proc Biol Sci. 2025 Aug;292(2053): 20250374

Evolutionary diversity of muscle OXPHOS efficiency in vitro across ectothermic vertebrates.

Rachel Lockridge Mueller, Lance C Li Puma, Michael W Itgen, Adam J Chicco.

  Oxidative metabolism meets the majority of vertebrate energy demands through the coupling of mitochondrial respiration to ATP production (OXPHOS). In endotherms, variations in OXPHOS coupling efficiency influence metabolic thermogenesis, locomotor economy and reactive oxygen species (ROS) generation. However, the extent of these variations and their functional implications in ectotherms are less clear. We measured mitochondrial oxygen consumption, ATP production and ROS production in permeabilized skeletal muscle fibres from salamanders, frogs and lizards representing ectotherm clades with low, medium and high standard metabolic rates (SMRs), respectively. Consistent with predicted associations with SMR, lizards had the highest capacities for muscle mitochondrial ATP production, while salamanders had the lowest. Unexpectedly, corresponding rates of oxygen consumption followed an opposite trend, reflecting 8.5-fold variations in OXPHOS coupling efficiency between salamanders (the lowest) and lizards (the highest). Intrinsic proton permeability of the inner mitochondrial membrane was the primary source of OXPHOS coupling variation across species, being highest in salamanders and lowest in lizards. Basal proton leak mediated by uncoupling proteins and the adenine nucleotide translocase was only seen in lizards, where it limits mitochondrial ROS production. We infer that diverse evolutionary selection pressures drive unexpectedly wide variations in muscle OXPHOS efficiency with different functional implications across ectotherm clades.

Keywords:  bioenergetics; high-resolution respirometry; mitochondria; oxidative phosphorylation; standard metabolic rate; vertebrates

DOI:  https://doi.org/10.1098/rspb.2025.0374
Sci Rep. 2025 Aug 20. 15(1): 30528

GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.

Adriana Ponton-Almodovar, Mary P Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.

  Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.

Keywords:  GPT2; Glutamine; Metabolism; Ovarian cancer

DOI:  https://doi.org/10.1038/s41598-025-15707-0
Crit Rev Oncol Hematol. 2025 Aug 20. pii: S1040-8428(25)00298-7. [Epub ahead of print]214 104910

Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors.

Pier Vitale Nuzzo, Silvia Rodrigues, Caroline Fidalgo Ribeiro, Isadora Ferrari Teixeira, Giuseppe Nicolo' Fanelli, Sara Bleve, Francesco Ravera, Hubert Pakula, Filippo Pederzoli, David M Nanus, Massimo Loda.

  Metabolic rewiring is a hallmark of cancer, enabling tumor cells to proliferate rapidly and survive under adverse conditions. Fatty acid synthase (FASN), a key enzyme in de novo lipogenesis, is significantly upregulated in various cancers and is associated with poor prognosis and increased tumor aggressiveness. This review examines the crucial role of FASN in cancer metabolism and evaluates the therapeutic potential of FASN inhibitors. We explore the metabolic pathways critically regulated by FASN and outline its structure, function, and regulatory mechanisms. Overexpression of FASN occurs in cancers such as lung, colon, brain, breast, and prostate, where clinical trials have either been conducted or are ongoing. Pharmacologic inhibition of FASN disrupts lipid biosynthesis, leading to accumulation of metabolic intermediates, induction of metabolic stress, and cell cycle arrest/apoptosis in cancer cells. Denifanstat (TVB-2640), the first-in-class selective FASN inhibitor with favorable pharmacokinetic properties, has demonstrated robust antitumor activity in preclinical models and encouraging results in early-phase clinical studies. Clinical evidence suggests that FASN blockade not only impairs tumor growth but also potentiates the efficacy of existing treatments, including chemotherapy and targeted agents, thereby supporting its integration into combination regimens. Future clinical optimization will require the identification of predictive biomarkers to guide patient selection and treatment stratification.

Keywords:  Cancer Metabolism; De Novo Lipogenesis (DNL); Denifanstat (TVB-2640); Fatty Acid Synthase (FASN) inhibitors; Lipid Biosynthesis; Metabolic Reprogramming

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104910
Mol Metab. 2025 Aug 21. pii: S2212-8778(25)00144-9. [Epub ahead of print]100 102237

ACAA1 knockout increases the survival rate of KPC mice by activating autophagy.

Ho Lee, Mingyu Kang, Sung Hoon Sim, Joon Hee Kang, Wonyoung Choi, Jung Won Chun, Woosol Hong, Chaeyoung Kim, Woojin Ham, Jeong Hwan Park, Eun-Byeol Koh, Yoon Jeon, Sang Myung Woo, Soo-Youl Kim.

   OBJECTIVES: We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.
METHODS: To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.
RESULTS: In normal cells, ACAA1 knockdown did not affect oxygen consumption. In contrast, in PDAC cells, ACAA1 knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, ACAA1 knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, ACAA1 knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. Acaa1a+/- mice showed a median survival increase of 3 weeks after crossing Acaa1a+/- with KPC mice (KrasG12D/+; Trp53R172H/+;Pdx1-Cre, a genetically engineered mice model for PDAC).
CONCLUSIONS: ACAA1 knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.

Keywords:  ACAA1; Autophagy; Fatty acid oxidation; Pancreatic cancer; Peroxisome

DOI:  https://doi.org/10.1016/j.molmet.2025.102237
Neurochem Res. 2025 Aug 23. 50(5): 275

Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes.

Gabriele Karger, Ralf Dringen.

  Astrocytes contain a high concentration of adenosine triphosphate (ATP) that enables these cells to perform their physiological functions in brain. To investigate the mechanisms involved in astrocytic ATP restoration, the ATP content of cultured primary rat astrocytes was first depleted by a preincubation with the mitochondrial uncoupler BAM15 before extracellular substrates and their combinations were applied to foster ATP restoration. To test for the contribution of the purine salvage pathway to synthesize new adenosine monophosphate (AMP) for ATP restoration, several purine nucleosides and purine bases as well as their combinations were applied. In the absence of glucose, partial ATP restoration was found for incubations with inosine and guanosine that was lowered by forodesine, an inhibitor of purine nucleoside phosphorylase. In glucose-fed cells, the coapplication of micromolar concentrations of adenine with inosine or guanosine, but not with ribose, accelerated ATP restoration in a concentration-dependent manner. By such treatments, 80% of the initial ATP content were restored within 40 min. The supporting effects of inosine and guanosine on ATP restoration were prevented by the presence of forodesine, demonstrating the contribution of purine nucleoside phosphorylase in the ATP restoration observed. These data demonstrate that ATP-deprived astrocytes need for rapid ATP restoration - in addition to glucose as energy substrate - an adenine source and inosine or guanosine as precursor for the ribose phosphate moiety of ATP.

Keywords:  ATP restoration; Astrocytes; Guanosine; Inosine; Purine nucleosides; Purine salvage pathway; Ribose

DOI:  https://doi.org/10.1007/s11064-025-04511-x
Blood. 2025 Aug 26. pii: blood.2025029132. [Epub ahead of print]

Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.

Cristiana O'Brien, Nirvana Nursimulu, Anit Tyagi, Rachel Culp-Hill, Andrea Arruda, Tracy Murphy, Mark D Minden, Andrew Kent, Brett M Stevens, Daniel A Pollyea, Kristin Hope, Sushant Kumar, Julie A Reisz, Angelo D'Alessandro, Courtney L Jones.

Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome. Circulating metabolites are influenced by patients' clinical status and can serve as accessible cancer biomarkers. To establish a resource of circulating metabolites in genetically diverse AML patients, we performed an unbiased metabolomic and lipidomic analysis of 231 diagnostic AML plasma samples prior to treatment with intensive chemotherapy. Intriguingly, circulating metabolites were highly associated with the mutation status within the AML cells. Further, lipids were associated with refractory status. We established a machine learning algorithm trained on chemo-refractory associated lipids to predict patient survival. Cox regression and Kaplan-Meier analysis demonstrated that the high-risk lipid signature predicted overall survival in this patient cohort. Impressively, the top lipid in the high-risk lipid signature, sphingomyelin (d44:1), was sufficient to predict overall survival in the original and an independent validation dataset. Overall, this research underscores the potential of circulating metabolites to capture AML heterogeneity and lipids to be used as potential AML biomarkers.

DOI: https://doi.org/10.1182/blood.2025029132
Nutr Diabetes. 2025 Aug 25. 15(1): 37

Ketogenic diet ameliorates MASLD via balancing mitochondrial dynamics and improving mitochondrial dysfunction.

Yuehua You, Hongbin Ni, Qin Ma, Lincheng Jiang, Jingshu Cai, Wenjun He, Xiaojing Lin, Kemeng Li, Zhuyun Wang, Weiyan Yan, Xiaoqiu Xiao, Li Ma.

BACKGROUND & AIMS: Ketogenic diet (KD) is recognized as an effective lifestyle intervention for managing metabolic dysfunction-associated steatotic liver disease (MASLD). This research aimed to assess the impact of KD on metabolic parameters in MASLD mice and elucidate the underlying mechanism.
METHODS: High-fat diet (HFD)-induced MASLD mice were subjected to KD for 2 weeks. Researchers measured hepatic fat, plasma Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) levels to assess metabolic changes. Hepatic mitochondrial dynamics were examined using transmission electron microscopy and Western blot. Mitochondrial functions were evaluated through Quantitative Polymerase Chain Reaction (qPCR) and measurement of ATP content. In vitro, HepG2 cells were treated with palmitate (PA), β-hydroxybutyric acid (β-OHB), and/or the mitochondrial fusion inhibitor MFI8 to study mitochondrial morphology, function, and lipid deposition.
RESULTS: KD feeding partially improved the MASLD phenotype and reduced Fission 1 protein (Fis1) and Dynamin-related protein 1 (Drp1) levels in the livers of MASLD mice. Additionally, KD ameliorated HFD-stimulated mitochondrial dysfunctions, as evidenced by elevated ATP levels and upregulation of key genes responsible for fatty-acid-oxidation. β-OHB mitigated PA-stimulated mitochondrial dysfunction and fission in HepG2 cells. Furthermore, β-OHB attenuated PA-stimulated lipid deposition, with this effect being counteracted by MFI8.
CONCLUSIONS: Our study suggests that a 2-week KD partially alleviates lipid deposition, restores mitochondrial dynamics balance, and improves mitochondrial dysfunctions in the livers of MASLD mice.

DOI: https://doi.org/10.1038/s41387-025-00391-w
Nature. 2025 Aug 20.

Quantitative imaging of lipid transport in mammalian cells.

Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, André Nadler.

Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.

DOI: https://doi.org/10.1038/s41586-025-09432-x
Int J Cancer. 2025 Aug 23.

Single-cell multi-omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC-unique features.

Zhijun Yu, Merel Derksen, Brigit M Te Pas, Sabrina Ladstätter, Rene Overmeer, Peter Brazda, Marc van de Wetering, Farzin Pourfarzad, Robert G J Vries, Wout Megchelenbrink, Christoph Bock, Lucia Altucci, Hendrik G Stunnenberg.

  Colorectal cancer (CRC) arises in the colorectal tissue driven by genetic disorder or the accumulation of somatic mutations, leading to abnormal epithelial cell growth. In this study, we employed single-nucleus multi-omics analysis, including single-nucleus RNA-seq and single-nucleus ATAC-seq, on over 100,000 high-quality nuclei to investigate the molecular landscape of both primary tissue and patient-derived organoids (PDOs). Our analysis showed that normal PDOs (N-PDOs) derived from tissue adjacent to tumors replicate the cellular composition and differentiation trajectory of colorectal crypts. In contrast, tumor PDOs (T-PDOs) showed patient-specific transcriptomic and epigenomic heterogeneity yet consistently maintained a stem cell-like state. T-PDOs retained the somatic mutation profile of the primary tumor while also exhibiting de novo mutations not detected in either the primary tumor or N-PDOs. Notably, inferred cell-cell interaction analysis highlighted the activin signaling pathway as a potential unique feature of fibroblast-epithelial interactions within the tumor microenvironment. This study provides a comprehensive view of the transition from normal to malignant colorectal epithelium and underscores the utility of PDOs as a faithful model for capturing both conserved and patient-specific features of colorectal cancer.

Keywords:  colorectal cancer (CRC); epigenomics; patient‐derived organoids (PDOs); single‐cell analysis; transcriptomics

DOI:  https://doi.org/10.1002/ijc.70103
Nature. 2025 Aug 27.

Mechanical confinement governs phenotypic plasticity in melanoma.

Miranda V Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Richard M White.

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.

DOI: https://doi.org/10.1038/s41586-025-09445-6
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 18. pii: S0925-4439(25)00371-0. [Epub ahead of print]1871(8): 168023

Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells.

Erika Matsuda, Shiho Hasebe, Takashi Matsuzaka, Akio Hayashi, Hiroshi Ohno, Kaori Motomura, Shotaro Sakka, Susumu Kohno, Hayato Muranaka, Minako Yamamura, Asuka Suzuki, Yoshinori Takeuchi, Yoshinori Osaki, Takafumi Miyamoto, Motohiro Sekiya, Hirohito Sone, Naoya Yahagi, Yoshimi Nakagawa, Satoshi Nitta, Shuya Kandori, Takahiro Kojima, Chiaki Takahashi, Hiroyuki Nishiyama, Hitoshi Shimano.

   OBJECTIVE: Increased de novo fatty acid (FA) synthesis is a hallmark of cancer. ELOVL FA elongase 6 (ELOVL6) catalyze chain elongation of C16 saturated and monounsaturated FAs into C18 species and has been implicated in several cancers. This study investigated the role of ELOVL6 in bladder cancer (BC).
METHODS: ELOVL6 expression was compared between BC and nontumor tissues. Human BC cell lines with ELOVL6-knockdown were assessed for proliferation and tumor growth. Metabolic and molecular alterations induced by ELOVL6 inhibition were analyzed using lipidomics and transcriptomics.
RESULTS: ELOVL6 expression was significantly higher in BC tissues than in controls. In fibroblast growth factor receptor 3 (FGFR3)-mutant BC cell lines, ELOVL6 knockdown suppressed cell growth in vitro and tumor progression in vivo. Lipidomic analysis showed a marked reduction in phosphatidylethanolamine following ELOVL6 knockdown, which was accompanied by lower mitochondrial complex I and II protein levels and impaired mitochondrial oxidative phosphorylation (OXPHOS). RNA sequencing revealed that mitochondrial dysfunction resulting from ELOVL6 knockdown triggered changes in extracellular matrix (ECM) remodeling gene expression and activation of the ECM-integrin-focal adhesion kinase (FAK) pathway, likely as a compensatory response to reduced cell proliferation.
CONCLUSION: ELOVL6 regulates lipid composition to preserve mitochondrial function, supporting cell growth and tumorigenesis in FGFR3-mutated BC. Targeting ELOVL6 may represent a novel therapeutic strategy for treating BC, particularly in tumors driven by FGFR3 mutations.

Keywords:  Bladder cancer (BC); ELOVL fatty acid elongase 6 (ELOVL6); Extracellular matrix (ECM); Fibroblast growth factor receptor 3 (FGFR3); Mitochondrial oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.1016/j.bbadis.2025.168023
Nat Protoc. 2025 Aug 22.

Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.

Rachel Williams, John Walsby-Tickle, Ingvild Comfort Hvinden, Isabelle Legge, Tereza Kacerova, KyoungEun Vicky Lee, Mariya Misheva, David Hauton, Judith B Ngere, John D Sidda, Elisabete Pires, Tom Cadoux-Hudson, James S O McCullagh.

The direct coupling of ion-exchange chromatography with mass spectrometry using electrochemical ion suppression creates a hyphenated technique with selectivity and specificity for the analysis of highly polar and ionic compounds. The technique has enabled new applications in environmental chemistry, food chemistry, forensics, cell biology and, more recently, metabolomics. Robust, reproducible and quantitative methods for the analysis of highly polar and ionic metabolites help meet a longstanding analytical need in metabolomics. Here, we provide step-by-step instructions for both untargeted and semi-targeted metabolite analysis from cell, tissue or biofluid samples by using anion-exchange chromatography-high-resolution tandem mass spectrometry (AEC-MS/MS). The method requires minimal sample preparation and is robust, sensitive and selective. It provides comprehensive coverage of hundreds of metabolites found in primary and secondary metabolic pathways, including glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid degradation and redox metabolism. An inline electrolytic ion suppressor is used to quantitatively neutralize OH- ions in the eluent stream, after chromatographic separation, enabling AEC to be directly coupled with MS. Counter ions are also removed during this process, creating a neutral pH, aqueous eluent with a simplified matrix optimal for negative ion MS analysis. Sample preparation through to data analysis and interpretation is described in the protocol, including a guide to which metabolites and metabolic pathways are suitable for analysis by using AEC-MS/MS.

DOI: https://doi.org/10.1038/s41596-025-01222-z
J Natl Cancer Inst. 2025 Aug 20. pii: djaf234. [Epub ahead of print]

Real-world generalizability of clinical trial cytomolecular risk in pediatric acute myeloid leukemia: a report from the REAL-AML cohort.

Daniel J Zheng, Gary Hettinger, Catherine Aftandilian, Kira Bona, Emi H Caywood, Anderson B Collier, Caitlin W Elgarten, Cody Gathers, Taumoha Ghosh, M Monica Gramatges, Meret Henry, Yuan-Shung V Huang, Yimei Li, Craig Lotterman, Kelly Maloney, Amir Mian, Tamara P Miller, Arunkumar Modi, Rajen Mody, Elaine Morgan, Regina Myers, Haley Newman, Jose Ortiz, Alix E Seif, Caroline Smith, Jamie Stokke, Xin Wang, Naomi Winick, Jennifer J Wilkes, Victor Wong, Richard Aplenc, Kelly D Getz.

Cytomolecular features critical for risk-stratified treatment determination in pediatric acute myeloid leukemia (AML) were expanded in Children's Oncology Group (COG) Phase III trial AAML1831 based on previous trials. It remains unknown whether the cytomolecular risk profiles are generalizable to the real-world. We addressed this knowledge gap using a nationally representative real-world cohort of 913 pediatric AML patients. Distributions of cytomolecular risk profiles and individual markers were comparable for trial-enrolled and non-enrolled patients, as well as across social drivers of trial enrollment (race/ethnicity, language, insurance, acuity). Compared to patients with only favorable cytomolecular markers (4-year OS 89.48%; 95% CI: 84.46%-92.95%), patients with both favorable and unfavorable (hazards ratio [HR] = 2.49, 95% CI : 1.18-5.23), neutral (HR = 4.33, 95% CI : 2.75-6.82), and only unfavorable (HR = 5.80, 95% CI: 3.70-9.11) markers all had increased hazards of death. Cytomolecular risk informed by trial data appears to be generalizable to the real-world setting in pediatric AML.

DOI: https://doi.org/10.1093/jnci/djaf234
Antioxidants (Basel). 2025 Aug 08. pii: 972. [Epub ahead of print]14(8):

Carnitine Shuttle and Ferroptosis in Cancer.

Ye-Ah Kim, Yoonsung Lee, Man S Kim.

  Ferroptosis is a unique type of regulated cell death characterized by iron-dependent lipid peroxidation, and it has emerged as a promising therapeutic target in cancer treatment. The carnitine shuttle system, which is crucial for transporting fatty acids across the mitochondrial membrane, has been identified as a key regulator of ferroptosis in cancer cells. This review investigates the intricate relationship between the carnitine shuttle and ferroptosis in cancer. We provide a comprehensive review of how the components of the carnitine system, including carnitine palmitoyltransferase 1A (CPT1A), carnitine palmitoyltransferase 2, and carnitine-acylcarnitine translocase, influence cellular redox homeostasis, fatty acid metabolism, and interact with proteins related to ferroptosis sensitivity. We discuss therapeutic implications of targeting the carnitine shuttle system, particularly CPT1A, to overcome ferroptosis resistance and enhance the efficacy of immunotherapy in various cancer types. This review offers further research directions, highlighting the crosstalk between the carnitine shuttle, ferroptosis, and various signaling pathways involved in cancer progression to improve cancer treatment.

Keywords:  CPT1A; cancer; carnitine shuttle; ferroptosis; lipid peroxidation; redox homeostasis

DOI:  https://doi.org/10.3390/antiox14080972
Cancers (Basel). 2025 Aug 12. pii: 2630. [Epub ahead of print]17(16):

Targeting of Mutant Isocitrate Dehydrogenase in Glioma: A Systematic Review.

Tyler A Lanman, L Nicolas Gonzalez Castro.

  Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication.

Keywords:  IDH inhibitor; IDH-mutant glioma; INDIGO; glioma; isocitrate dehydrogenase; ivosidenib; precision oncology; primary brain tumors; systematic review; vorasidenib

DOI:  https://doi.org/10.3390/cancers17162630
Int J Surg. 2025 Aug 27.

Succinylation - encoded metabolic codes: cracking the molecular logic of cellular adaptation.

Yipeng Cong, Xiaoman Zhang, Zian Wang, Zhongren Cui, Chengming Li, Yongzheng Han, Wen Deng, Xingxuan Zhou, Hongliang Wu, Jingsong Sun, Hongbo Fan, Guangzhen Wu.

   GRAPHICAL ABSTRACT: Lysine succinylation is the covalent modification of succinyl groups (-CO-CH ₂ -CH ₂ -COOH) to lysine residues of target proteins, which causes conformational changes and regulates their functional states. In this figure, mitochondria are used as the metabolic hub to summarize the production and consumption of succinyl-CoA in the TCA cycle and mediate the succinylation of key enzymes and transcription factors such as PDH, SDH, GLUD1, HMGCS2, and FEN1. The central region showed the negative regulation of SIRT5/SIRT7 and the positive regulation of KAT2A, alpha-KGDH, CPT1A, HAT1, and other acyltransferases. The lower part of the figure highlights that succinylation promotes tumor cell hypoxic adaptation and immune escape by stabilizing HIF-1α, inducing ROS production, and SDH dysfunction. TCA, Tricarboxylic acid cycle PDH, Pyruvate dehydrogenase SDH, Succinate dehydrogenase GLUD1, Glutamate dehydrogenase 1 HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2 FEN1, Flap endonuclease 1, SIRT, Sirtuin family proteins, KAT2A, Lysine acetyltransferase 2A alpha-KGDH, Alpha-ketoglutarate dehydrogenase CPT1A, Carnitine palmitoyltransferase 1A HAT1, Histone acetyltransferase 1 HIF-1α, Hypoxia-inducible factor 1 alpha ROS Reactive oxygen species.This figure was created by Biorender.com.(https://BioRender.com).

Keywords:  dessuccinylase tricarboxylic acid cycle; immune escape; succinylation; tumor microenvironment; tumorigenesis

DOI:  https://doi.org/10.1097/JS9.0000000000003249
Biol Chem. 2025 Jun 24.

Biogenesis and function of the mitochondrial solute carrier (SLC25) family in yeast.

Celina Nauerz, Ophry Pines, Johannes M Herrmann.

  The mitochondrial solute carrier family, also called SLC25 family, comprises a group of structurally and evolutionary related transporters that are embedded in the mitochondrial inner membrane. About 35 and 53 mitochondrial carrier proteins are known in yeast and human cells, respectively, which transport nucleotides, metabolites, amino acids, fatty acids, inorganic ions and cofactors across the inner membrane. They are proposed to function by a common rocker-switch mechanism, alternating between conformations that expose substrate-binding pockets to the intermembrane space (cytoplasmic state) and to the matrix (matrix state). The substrate specificities of both states differ so that carriers can operate as antiporters, symporters or uniporters. Carrier proteins share a characteristic structure comprising six transmembrane domains and expose both termini to the intermembrane space. Most carriers lack N-terminal presequences but use carrier-specific internal targeting signals that direct them into mitochondria via a specific import route, known as the 'carrier pathway'. Owing to their hydrophobicity and aggregation-prone nature, the mistargeting of carriers can lead to severe proteotoxic stress and diseases. In this review article, we provide an overview about the structure, biogenesis and physiology of carrier proteins, focusing on baker's yeast where their biology is particularly well characterized.

Keywords:  TIM22 complex; membrane transport; metabolism; mitochondria; protein translocation

DOI:  https://doi.org/10.1515/hsz-2025-0152
Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00936-2. [Epub ahead of print]44(9): 116165

Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain.

Zehao Zhang, Alexander Epstein, Chloe Schaefer, Abdulraouf Abdulraouf, Weirong Jiang, Wei Zhou, Junyue Cao.

  Caloric restriction (CR) is a well-studied intervention that extends lifespan and slows cognitive decline across species, yet the specific cell populations and molecular pathways involved remain elusive. In this study, we profiled >500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in >300 cellular states and 11 brain regions. CR delayed expansion of inflammatory cell populations, preserved neural precursor cells, and broadly reduced the expression of aging-associated genes involved in cellular stress, senescence, inflammation, and DNA damage. CR restored the expression of region-specific genes linked to cognitive function, myelin maintenance, and circadian rhythm. In summary, we provide a high-resolution spatiotemporal map of the aging mouse brain's response to CR, detailing precise cellular and molecular mechanisms behind its neuroprotective effects.

Keywords:  CP: Genomics; CP: Metabolism; brain aging; caloric restriction; cellular senescence; neurogenesis; neuroinflammation; rejuvenation; single-cell transcriptomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116165
Cell. 2025 Aug 22. pii: S0092-8674(25)00914-6. [Epub ahead of print]

Mitochondrial activity tunes nociceptor resilience to excitotoxicity.

Lin Yuan, Navdeep S Chandel, David Julius.

  The capsaicin receptor, TRPV1, mediates the detection of noxious chemical and thermal stimuli by nociceptors, primary sensory neurons of the pain pathway. Overactivation of TRPV1 leads to cellular damage or death through calcium entry and excitotoxicity. We have exploited this phenomenon to conduct a systematic analysis of excitotoxicity through a genome-wide CRISPRi screen, thereby revealing a comprehensive network of regulatory pathways. We show that decreased expression of mitochondrial electron transport chain (ETC) components protects against capsaicin-induced toxicity and other challenges by mitigating both calcium imbalance and the generation of mitochondrial reactive oxygen species via distinct pathways. Moreover, we confirm the regulatory roles of the ETC in sensory neurons through gain-of-function and loss-of-function experiments. Interestingly, TRPV1+ sensory neurons maintain lower expression of ETC components and can better tolerate excitotoxicity and oxidative stress compared with other sensory neuron subtypes, implicating ETC tuning as an intrinsic cellular strategy that protects nociceptors against excitotoxicity.

Keywords:  CRISPRi; ROS; antioxidants; cell death; chemical genetic screen; electron transport chain; excitotoxicity; mitochondria; nociceptors; sensory neurons

DOI:  https://doi.org/10.1016/j.cell.2025.07.048
Biochem Pharmacol. 2025 Aug 22. pii: S0006-2952(25)00540-4. [Epub ahead of print]242(Pt 1): 117275

Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.

Hui Wang, Xiandeng Li, Haitao Hu, Zhan Gao.

  Glutaminase 1 (GLS1) is a critical enzyme in glutamine metabolism, supporting both energy production and biosynthesis in tumor cells. Inhibitors targeting GLS1 have emerged as promising metabolic therapies. Notably, it exhibits antiproliferative and pro-apoptotic effects in various cancers. This review systematically discusses GLS1's structure and function, the major classes of inhibitors, and the principles behind their design. It also explores the molecular mechanisms underlying GLS1 inhibition, including disruption of glutamine metabolism, induction of oxidative stress, and modulation of key signaling pathways. Furthermore, we evaluated the current clinical applications and therapeutic potential of GLS1 inhibitors in cancer and metabolic disorders. Themes such as drug safety, resistance development, and patient stratification are also addressed. Future research should highlight the potential of combination therapies and precision medicine approaches. Collectively, targeting GLS1 represents a promising strategy with significant translational potential in metabolism-related diseases.

Keywords:  Cancer; GLS1; GLS1 inhibitors; Glutamine metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bcp.2025.117275
Cells. 2025 Aug 14. pii: 1254. [Epub ahead of print]14(16):

Investigation and Distinction of Energy Metabolism in Proliferating Hepatocytes and Hepatocellular Carcinoma Cells.

Julia Nerusch, Gerda Schicht, Natalie Herzog, Jan-Heiner Küpper, Daniel Seehofer, Georg Damm.

  Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte® hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased HIF1A expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced BDH1 levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and BDH1, reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis.

Keywords:  BDH1; HIF1A; HepaFH3; c-MYC; glycolysis; hepatocellular carcinoma; ketone body metabolism; liver regeneration; metabolic reprogramming; tumor markers

DOI:  https://doi.org/10.3390/cells14161254
Cell Rep Med. 2025 Aug 19. pii: S2666-3791(25)00377-5. [Epub ahead of print] 102304

Image-based drug screening combined with molecular profiling identifies signatures and drivers of therapy resistance in pediatric AML.

Ben Haladik, Margarita Maurer-Granofszky, Peter Zoescher, Raul Jimenez-Heredia, Alexandra Frohne, Anna Segarra-Roca, Chloe Casey, Felix Kartnig, Sarah Giuliani, Christina Rashkova, Peter Repiscak, Michael N Dworzak, Giulio Superti-Furga, Kaan Boztug.

  Despite recent advances in the understanding of the genomic landscape of pediatric acute myeloid leukemia (pedAML), targeted treatments are only available for selected genomic alterations, and the functional link between genotype and outcome remains partially elusive. Functional precision medicine approaches to investigate treatment resistance and patient risk have not been applied systematically for pedAML. Here, we describe an advanced functional screening platform combining high-content imaging and deep learning-based phenotyping. In 45 patients with pedAML, we identify BCL2 and FLT3 inhibitors and standard chemotherapy as major drivers of the chemosensitivity landscape, reveal substantial differential sensitivities between risk groups, and may effectively predict individual measurable residual disease and patient risk. Integration with genomic and epigenomic data uncovers a chemotherapy-resistant primitive state vulnerable to combined BCL2 and MDM2 inhibition and HDAC inhibition. Overall, we identify early signatures of therapy resistance across genetic subgroups and prioritize targeted treatments for these functionally and epigenetically defined patient subsets.

Keywords:  cellular differentiation; data integration; deep learning; drug screening; epigenetics; high-content imaging; pediatric AML; precision medicine

DOI:  https://doi.org/10.1016/j.xcrm.2025.102304