bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–06–15
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.
  2. Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.
  3. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
  4. Mitochondrial molecule has unexpected role in tissue healing.
  5. GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
  6. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  7. Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
  8. Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
  9. Development of a Novel Biomarker Platform for Profiling Key Protein-Protein Interactions to Predict the Efficacy of BH3-Mimetic Drugs.
  10. An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
  11. Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
  12. The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.
  13. Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
  14. Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.
  15. Modulation of copper homeostasis and cuproptosis by PDHA1 in acute myeloid leukemia.
  16. Dynamic evolution of venetoclax resistance in acute myeloid leukemia unveiled by longitudinal single-cell RNA-seq.
  1. bioRxiv. 2025 Jun 07. pii: 2025.06.06.657881. [Epub ahead of print]
    Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.
    Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana da Costa Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Sung-Ah Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.
      Resistance to combination regimens containing the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively utilized agent. We previously established the anti-leukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supported leukemic survival and resistance to BH3 mimetics. Here, we report the anti-leukemic efficacy and mechanisms of co-targeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML dataset revealed a positive relationship between increased AC gene expression and venetoclax resistance. Targeting AC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was equipotent to the combination of venetoclax + cytarabine at reducing cell viability when evaluated ex vivo across a cohort of 71 primary AML patient samples. Mechanistically, SACLAC + venetoclax increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Collectively, these data demonstrate the efficacy of co-targeting AC and BCL-2 in AML and rationalize targeting AC as a therapeutic approach to overcome venetoclax resistance.
    DOI:  https://doi.org/10.1101/2025.06.06.657881
  2. Haematologica. 2025 Jun 12. 0
    Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia.
    Junji Ikeda, Hiroyoshi Kunimoto, Yusuke Saito, Shin-Ichi Tsujimoto, Masanobu Takeuchi, Ayaka Miura, Takayuki Kurosawa, Koichi Murakami, Ikuma Kato, Megumi Funakoshi-Tago, Akihiko Yokoyama, Norio Shiba, Souichi Adachi, Daisuke Tomizawa, Tomohiko Tamura, Shuichi Ito, Hideaki Nakajima.
      Acute myeloid leukemia (AML) patients with high PRDM16 expression frequently experience induction failure and have a poor prognosis. However, the molecular mechanisms underlying these clinical features remain elusive. We found that murine AML cells transformed by MLL::AF9 fusion and oncogenic short-isoform Prdm16 overexpression (hereafter, MF9/sPrdm16) exhibited resistance to cytarabine (AraC), but not to anthracycline, both in vitro and in vivo. Intriguingly, MF9/sPrdm16 cells displayed a gene expression signature of high oxidative phosphorylation (OxPHOS) and increased mitochondrial respiration. The inhibition of mitochondrial respiration with metformin or tigecycline abrogated AraC resistance in MF9/sPrdm16 cells via an energetic shift toward low OxPHOS status. Furthermore, sPrdm16 upregulated Myc and the glutamine transporter Slc1a5, activating TCA cycle and glutaminolysis. Of note, both OxPHOS and MYC-target gene signatures were significantly enriched in AML patient samples with high PRDM16 expression. Together, we showed that PRDM16 overexpression activates mitochondrial respiration through metabolic reprogramming via MYC-SLC1A5-Glutaminolysis axis, thereby conferring AraC resistance on AML cells. These results suggest that targeting mitochondrial respiration might be a novel treatment strategy to overcome chemoresistance in AML patients with high PRDM16 expression.
    DOI:  https://doi.org/10.3324/haematol.2024.287265
  3. Nature. 2025 Jun 11.
    Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
    Dylan Calhoon, Lingjie Sang, Fubo Ji, Divya Bezwada, Sheng-Chieh Hsu, Feng Cai, Nathaniel Kim, Amrita Basu, Renfei Wu, Anastasia Pimentel, Bailey Brooks, Konnor La, Ana Paulina Serrano, Daniel L Cassidy, Ling Cai, Vanina Toffessi-Tcheuyap, Maryam E Moussa, Winnie Uritboonthai, Linh Truc Hoang, Meghana Kolli, Brooklyn Jackson, Vitaly Margulis, Gary Siuzdak, James Brugarolas, Ian Corbin, Derek A Pratt, Ryan J Weiss, Ralph J DeBerardinis, Kıvanç Birsoy, Javier Garcia-Bermudez.
      Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41586-025-09162-0
  4. Nature. 2025 Jun 11.
    Mitochondrial molecule has unexpected role in tissue healing.
    Ram P Chakrabarty, Navdeep S Chandel.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01583-1
  5. Cell Rep. 2025 Jun 09. pii: S2211-1247(25)00545-5. [Epub ahead of print]44(6): 115774
    GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
    Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, Chuanzhao Zhang.
      KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.
    Keywords:  CP: Cancer; CP: Metabolism; GCLM; KRAS mutation; ferroptosis; glutamate-cysteine ligase modifier; pancreatic cancer; protein lactylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115774
  6. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  7. Cell Metab. 2025 Jun 09. pii: S1550-4131(25)00265-7. [Epub ahead of print]
    Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
    Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei, Jun Xia, Yanxin Xu, Jonathan G Van Vranken, Michael Mazzola, Lei Chen, Catherine Rhee, Tiancheng Fang, Tsuyoshi Fukushima, Leanne C Sayles, Matthew Diaz, J Alex B Gibbons, Raul Mostoslavsky, Steven P Gygi, Zhixun Dou, David B Sykes, Ruslan I Sadreyev, E Alejandro Sweet-Cordero, David T Scadden.
      Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.
    Keywords:  ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.009
  8. bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]
    Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.
    DOI:  https://doi.org/10.1101/2025.05.25.655566
  9. Cancers (Basel). 2025 May 31. pii: 1852. [Epub ahead of print]17(11):
    Development of a Novel Biomarker Platform for Profiling Key Protein-Protein Interactions to Predict the Efficacy of BH3-Mimetic Drugs.
    Andrew J Kinloch, Faiyaz Rahman, Bahriye Karakas, Muhammad Shahid, Bora Lim, Stephanie J Bouley, James A Walker, Erinna F Lee, Walter D Fairlie, Kevin R Kelly, Michael H Cardone.
      One of the hallmarks of cancer cells is their failure to respond to the cellular mechanism of apoptosis. The B-cell lymphoma 2 (BCL-2) family of proteins regulate apoptosis. Their ability to do so can be measured using several methods that in turn anticipate the fate of the cancer cell in response to apoptosis-inducing treatment. These assays ultimately identify the readiness of the cancer cell to undergo apoptosis, which is referred to as the mitochondrial priming state. These metrics, however, have been challenging to implement in the clinic. Methods: Here, we describe a unique method that relies on a panel of novel conformation-specific antibodies (termed PRIMAB) that can directly measure the mitochondrial priming state. These reagents are highly specific for complexes of their corresponding pro-survival protein interactions with the pro-apoptotic protein BIM. These BIM-containing heterodimeric complexes have long been established as hallmarks of primed cancer cells. Results: Using clinically amenable assay formats, PRIMABs were shown to detect the presence of these anti-apoptotic-pro-apoptotic complexes and their disruption by BH3-mimetic drugs. Moreover, PRIMABs were able to detect a shift in priming status following BH3-mimetic treatment, a factor associated with resistance to these drugs. In a panel of AML patient samples, we report a wide range of priming levels for each PRIMAB complex, demonstrating the potential for heterogeneity in responses. We also show that PRIMABs could be predictive of outcomes for AML patients following cytarabine-based treatment. Conclusions: PRIMABs provide novel and useful tools for cancer research and for clinical implementation as reagents providing predictive tests for treatment response.
    Keywords:  AML; BH3 domain; BH3 mimetics; PRIMAB; apoptosis; flow cytometry; mitochondrial priming
    DOI:  https://doi.org/10.3390/cancers17111852
  10. EMBO Rep. 2025 Jun 09.
    An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
    Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier.
      The mitochondrial F1F0-ATP synthase is crucial for maintaining the ATP/ADP balance which is critical for cell metabolism, ion homeostasis and cell proliferation. This enzyme, conserved across evolution, is found in the mitochondria or chloroplasts of eukaryotic cells and the plasma membrane of bacteria. In vitro studies have shown that the mitochondrial F1F0-ATP synthase is reversible, capable of hydrolyzing instead of synthesizing ATP. In vivo, its reversibility is inhibited by the endogenous peptide If1 (Inhibitory Factor 1), which specifically prevents ATP hydrolysis in a pH-dependent manner. Despite its presumed importance, the loss of If1 in various model organisms does not cause severe phenotypes, suggesting its role may be confined to specific stress or metabolic conditions yet to be discovered. Our analyses indicate that inhibitory peptides are crucial in mitigating mitochondrial depolarizing stress under glyco-oxidative metabolic conditions. Additionally, we found that the absence of If1 destabilizes the nuclear-encoded free F1 subcomplex. This mechanism highlights the role of If1 in preventing harmful ATP wastage, offering new insights into its function under physiological and pathological conditions.
    Keywords:  ATP Synthase; Bioenergetics; F1 Subcomplex; IF1; Mitochondria
    DOI:  https://doi.org/10.1038/s44319-025-00430-8
  11. PLoS One. 2025 ;20(6): e0325509
    Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
    Floriana Jessica Di Paola, Luiza Hd Cardoso, Efterpi Nikitopoulou, Bianca Kulik, Sandra Rühl, Alexander Eva, Natascha Sommer, Thomas Linn, Erich Gnaiger, Klaus Failing, Kathrin Büttner, Christian Frezza, Sybille Mazurek.
      Mitochondrial glycerol 3-P dehydrogenase (mtG3PDH) plays a significant role in cellular bioenergetics by serving as a rate-limiting element in the glycerophosphate shuttle, which connects cytosolic glycolysis to mitochondrial oxidative metabolism. mtG3PDH was identified as an important site of electron leakage leading to ROS production to the mitochondrial matrix and intermembrane space. Our research focused on the role of two published mtG3PDH inhibitors (RH02211 and iGP-1) on the proliferation and metabolism of PC-3 and DU145 prostate cancer cells characterized by different mtG3PDH activities. Since pyruvate as a substrate of lactate dehydrogenase (LDH) may represent an escape mechanism for the recycling of cytosolic NAD+ via the glycerophosphate shuttle, we investigated the effect of pyruvate on the mode of action of the mtG3PDH inhibitors. Extracellular pyruvate weakened the growth-inhibitory effects of RH02211 and iGP-1 in PC-3 cells but not in DU145 cells, which correlated with higher H-type LDH and lower mitochondrial glutamate-oxaloacetate transaminase in DU145 cells. In the pyruvate-low medium, the strength of inhibition was more pronounced in PC-3 cells, characterized by higher mtG3PDH activities compared to DU145 cells. Pyruvate conversion rates (production in pyruvate-low and consumption in pyruvate-high PC-3 cells) were not impaired by RH02211 and iGP-1, suggesting that the conversion of extracellular pyruvate to lactate was not the primary factor responsible for the weakening effect of extracellular pyruvate on the RH02211-induced inhibition of PC-3 proliferation. In pyruvate-high PC-3 cells, the intracellular glycerol-3-P and dihydroxyacetone-P concentrations were consistent with an inhibition of mtG3PDH. In contrast, in pyruvate-low cells, the concentrations of these metabolites suggested an activation of mtG3PDH in parallel with an impairment of cytosolic G3PDH by RH02211. Of all metabolic characterizations recorded in this study (fluxes, intracellular intermediates, O2 consumption and H2O2 production), the decrease in glutaminolysis correlated best with the RH02211-induced inhibition of proliferation in pyruvate-low and pyruvate-high PC-3 cells.
    DOI:  https://doi.org/10.1371/journal.pone.0325509
  12. Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00461-7. [Epub ahead of print]
    The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.
    Yumeng Zu, Chou Wu, Feifei Li, Hong Yao, Yuyue Xia, Ruoxi Zhang, Lulu Li, Shuangquan Chen, Qi Shi, Shuang Xi, Huanhuan Pang, Minghui Liu, Leibo Wang, Sandi Terpack, Weihua Wang, She Chen, Hong Zhang, Yibing Wang, Maojun Yang, Shanjin Huang, Fuling Zhou, Yu Tang, Zeping Hu, Shilong Fan, Yefeng Tang, Young-Sam Lee, Gelin Wang.
      Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.
    Keywords:  AMP; ATP; NAD(+) biosynthesis; NAMPT; energy stress; fasting; ischemia; purine synthesis
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.022
  13. bioRxiv. 2025 Jun 07. pii: 2025.06.06.658169. [Epub ahead of print]
    Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Johanna Ten Hoeve, Kevin J Williams, Tolga Sever, Isabela Fuentes, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumours. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone body production. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone body production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumour progression. In contrast, inhibition of fatty acid oxidation did limit adenomatous formation. These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1101/2025.06.06.658169
  14. Cancers (Basel). 2025 May 23. pii: 1751. [Epub ahead of print]17(11):
    Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.
    Kai Xu, Pratham Shah, Dhruvi Makhanasa, Md Wasim Khan.
      Branched-chain amino acids (BCAAs) are essential for protein synthesis and play a crucial role in activating signaling pathways that regulate cell growth and division. Growing evidence reveals their complex role in cancer, particularly in how they support the metabolic reprogramming of tumor cells. BCAAs contribute to an environment that promotes tumor growth and survival by affecting energy balance and key cellular signaling networks. This review highlights recent advances in understanding how BCAAs influence cancer metabolism, emphasizing their dual function as both essential nutrients and sources of metabolic fuel. It also explores how BCAAs interact with other metabolic pathways, revealing potential targets for therapy. By uncovering these cancer-specific dependencies on BCAAs, this work points to promising strategies for disrupting tumor progression and developing new treatment approaches.
    Keywords:  BCAAs; cancer metabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers17111751
  15. Discov Oncol. 2025 Jun 10. 16(1): 1044
    Modulation of copper homeostasis and cuproptosis by PDHA1 in acute myeloid leukemia.
    Tianping Chen, Nan Wei, Wenxiu Lv, Lijun Qu, Qian Qu, Chaohong Wu, Yuan Ling, Haipeng Liu, Hongjun Liu.
       BACKGROUND: Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis. Recent studies highlight cuproptosis, a copper-dependent cell death mechanism, as a potential therapeutic target in cancers. This study investigates the expression and functional significance of CRGs, particularly PDHA1, in AML progression and cuproptosis regulation METHODS: We integrated bioinformatics analysis and experimental validation. Bioinformatics analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) was performed to identify CRGs associated with AML. Among these, pyruvate dehydrogenase E1 alpha subunit (PDHA1) was selected for further investigation. AML cell lines (Kasumi-1, U937, etc.) were treated with Elesclomol-CuCl2 to induce cuproptosis. PDHA1 was overexpressed via transfection, and its effects on proliferation (CCK-8, spheroid formation), apoptosis (flow cytometry), cell cycle (propidium iodide staining), and copper ion content were assessed. qPCR, Western blot, and glutathione (GSH) assays evaluated gene/protein expression and redox status.
    RESULTS: Our analysis revealed that PDHA1 is significantly downregulated in AML tissues compared to normal controls. Overexpression of PDHA1 in AML cell lines led to reduced cell proliferation, increased apoptosis, and G1 phase arrest. Additionally, PDHA1 overexpression was associated with downregulation of Cyclins D1 and D3. Importantly, PDHA1 overexpression enhanced the sensitivity of AML cells to copper-induced cytotoxicity, indicating its potential to modulate cuproptosis.
    CONCLUSION: These findings suggest that PDHA1 regulates cuproptosis by modulating copper metabolism and may serve as a potential therapeutic target and biomarker in AML.
    Keywords:  Acute myeloid leukemia; Cell cycle arrest; Cuproptosis; PDHA1
    DOI:  https://doi.org/10.1007/s12672-025-02814-7
  16. Cancer Lett. 2025 Jun 05. pii: S0304-3835(25)00420-3. [Epub ahead of print]628 217853
    Dynamic evolution of venetoclax resistance in acute myeloid leukemia unveiled by longitudinal single-cell RNA-seq.
    Huan Lu, Huafeng Wang, Qiwei Wang, Deyu Huang, Yingli Han, Hui Wang, Penglei Jiang, Xinyue Qian, Liping Mao, Min Yang, Hongyan Tong, Jie Jin, Pengxu Qian, Hong-Hu Zhu.
      Despite extensive investigation into venetoclax resistance mechanisms in acute myeloid leukemia (AML), the dynamics of bone marrow (BM) microenvironment remodeling during venetoclax-based therapies remain poorly characterized at single-cell resolution. Using paired single-cell RNA sequencing of BM specimens from AML patients undergoing DAV therapy (venetoclax/decitabine/cytarabine; pre- vs post-treatment), we systematically mapped therapy-induced transcriptional reprogramming, regulatory network alterations, and niche crosstalk across clinical response subgroups. Our analysis revealed two pivotal mechanisms governing therapeutic outcomes: First, pre-existing immune-activating niches marked by elevated HLA class I presentation synergized with therapy-enhanced CD8+ T cell cytotoxicity and reduced tumor-promoting stroma-leukemia interactions to facilitate favorable responses. Second, responder leukemic cells exhibited transposable element (TE)-associated type I interferon signaling upregulation. Primitive leukemic clones displayed IMPDH2-high states linked to BCL2 inhibitor sensitivity, while resistant monocytic populations upregulated glycolysis and MCL1 to bypass BCL2 dependence. Leveraging these insights, we established a prognostic signature predicting patient responses to venetoclax-based therapies, validated in independent cohorts (Tumor Profiler, BeatAML2). High-risk patients identified by this signature demonstrated heightened sensitivity to IGF-1R inhibition. Functional validation in an established resistant cell line model confirmed that IGF-1R inhibition synergized with DAV by suppressing glucose uptake and differentiation. This study provides a comprehensive single-cell atlas of BM microenvironment evolution during venetoclax-based therapy, proposes a prognostic biomarker, and identifies a clinically actionable strategy to overcome therapeutic resistance in AML.
    Keywords:  Acute myeloid leukemia; DAV treatment; Single-cell RNA sequencing; Therapeutic resistance; Venetoclax
    DOI:  https://doi.org/10.1016/j.canlet.2025.217853
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