bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–03–15
twelve papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer.
  2. Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
  3. Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.
  4. Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking.
  5. Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.
  6. Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
  7. β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
  8. Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
  9. Ageing promotes metastasis via activation of the integrated stress response.
  10. Immune-metabolic plasticity in AML: Prognostic roles of aCTLs (activated Cytotoxic T Cells) and Kynurenine.
  11. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  12. Addition of Venetoclax to Azacitidine Did Not Improve Survival in Acute Myeloid Leukemia and Was Not Well Tolerated: Real World Experience.
  1. Cancer Biol Med. 2026 Mar 12. pii: j.issn.2095-3941.2025.0444. [Epub ahead of print]
    Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer.
    Xin Jin, Albert M Li, Man Zhao, Haowen Jiang, Yiren Xiao, Michaela Yip, Stavros Melemenidis, Scott Jackson, Yanan Yang, Cathyrin Simmermaker, Meng-Ning Zhou, Subarna Sinha, Daniel J Cuthbertson, Erinn B Rankin, Jiangbin Ye.
       OBJECTIVE: The mitochondrial serine catabolic pathway (MSCP) supports tumor proliferation and metastasis, yet no therapies target the MSCP. Because cancer cells rely on the MSCP when respiration is suppressed, we hypothesized that reactivating respiration would inhibit the MSCP.
    METHODS: Mitochondrial respiration was activated in triple negative breast cancer (TNBC) cells using uncouplers [niclosamide ethanolamine (NEN) and BAM15]. Metabolic activity through the MSCP was assessed using U-13C-serine tracing and expression of key MSCP enzymes (SHMT2, MTHFD2, and MTHFD1L) were evaluated at the mRNA and protein levels. The NAD+:NADH ratio and 2-hydroxyglutarate (2-HG) levels were determined using liquid chromatography-mass spectrometry. The role of m6A RNA demethylase fat mass and obesity-associated protein (FTO) in regulating MSCP enzymes was examined using pharmacologic and genetic approaches. The therapeutic potential of mitochondrial uncoupling was tested in vivo using a lung metastasis model.
    RESULTS: Activation of mitochondrial respiration with NEN or BAM15 inhibited MSCP activity, as indicated by reduced labeling of glycine and purines from U-13C-serine. Mitochondrial uncoupling markedly decreased the levels of SHMT2, MTHFD2, and MTHFD1L protein, despite unchanged or elevated mRNA levels. This post-transcriptional suppression was mediated by an increased NAD+:NADH ratio, leading to reduced 2-HG production and subsequent activation of FTO. Inhibition of FTO, either pharmacologically or genetically, restored MSCP enzyme protein levels. Dietary mitochondrial uncoupling significantly suppressed lung metastasis in vivo.
    CONCLUSIONS: The findings herein demonstrated that mitochondrial uncouplers inhibit MSCP through FTO-dependent m6A demethylation. This work identified mitochondrial uncoupling as a novel and promising therapeutic approach for promoting m6A demethylation and targeting MSCP in metastatic breast cancer.
    Keywords:  FTO; Mitochondria uncoupler; breast cancer; m6A; metastasis; one-carbon unit metabolism; serine catabolism
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0444
  2. Cancer Res. 2026 Mar 12.
    Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
    Chun-Hao Pan, Yinghuan Lyu, Monisankar Ghosh, Md Afjalus Siraj, Robert Tseng, Nina V Chaika, John D Haley, Bahman Khalvatifahlylani, David A Tuveson, Hardik D Patel, Muaz Faruque, Girish H Rajacharya, Katie L Donnelly, Cindy V Leiton, Carlos Mejia Arbelaez, Haoting Chen, Sumedha Chowdhury, Shayan Sarkar, Lyanne Delgado Coka, Lucia Roa-Peña, Michael Horowitz, Natalia Marchenko, Pankaj K Singh, Kenneth R Shroyer, Luisa F Escobar-Hoyos.
      The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. Here, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intra-mitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization sequence (MLS) recognized by the translocase of the outer mitochondrial membrane 20 (TOM20). In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analog and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of DHODH combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17⁺ but not K17⁻ PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17⁺ basal-like PDACs that can be therapeutically targeted.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4534
  3. Cell Rep Med. 2026 Mar 10. pii: S2666-3791(26)00080-7. [Epub ahead of print] 102663
    Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.
    Catherine Kirkpatrick, Charles M Quick, Steven R Post, Yuet-Kin Leung, Ruud P M Dings, Chrystal M Paulos, Lyle Burdine, Yong-Chen William Lu.
      T cells are pivotal to cancer immunotherapy, yet chemotherapy may erode their fitness. Using a single-cell technique, we show that exposure to two widely used chemotherapeutic agents, 5-FU (5-fluorouracil) and cisplatin, induces non-synonymous mitochondrial DNA (mtDNA) mutations in T cells. Notably, nearly all detected mtDNA mutations are transition mutations. Like the effects observed in genomic DNA mutations, the impacts of mtDNA mutations in T cells appear to be random. Some T cells with mtDNA mutations concentrate in clusters associated with gene markers, while others do not. Additionally, several mtDNA mutations are found in the fraction of treated T cells with low mitochondrial activity, suggesting their potential effect on mitochondrial function. Importantly, mtDNA mutations are detected in tumor-infiltrating T cells from patients with colorectal cancer who received chemotherapy. Our findings uncover an unappreciated consequence of chemotherapy on T cell mitochondria, and these results raise concerns about administering immunotherapy and chemotherapy concurrently.
    Keywords:  T cell biology; cancer immunotherapy; combination therapy; mitochondrial biology; single-cell genomics
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102663
  4. Theranostics. 2026 ;16(9): 4865-4882
    Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking.
    Yen-Dun Tony Tzeng, Emmanuel Naveen Raj, Shih-Hsuan Cheng, Su-Boon Yong, Shih-Chieh Lin, Ren-Wang Peng, Chia-Jung Li.
      The clinical efficacy of targeted cancer therapies is persistently undermined by the emergence of acquired resistance. While secondary genetic mutations are well-characterized, increasing evidence implicates non-genetic metabolic reprogramming as a primary driver of survival during the initial phase of treatment. This review elucidates the concept of "Metabolic Shapeshifters"-specifically, drug-tolerant persister cells (DTPs) that dynamically adapt their bioenergetic machinery to evade therapeutic stress. We examine the plasticity between the classical Warburg Effect and the Reverse Warburg Effect, describing how DTPs shift from a glucose-addicted proliferative state to a quiescent phenotype strictly reliant on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation. Crucially, we highlight a paradigm shift from intracellular reprogramming to intercellular "organelle parasitism." Recent breakthroughs demonstrate that DTPs actively hijack functional mitochondria from infiltrating immune cells and the stromal network via tunneling nanotubes (TNTs). This predatory behavior not only restores the tumor's respiratory capacity but also induces metabolic exhaustion in T cells, thereby orchestrating immune evasion. Finally, we delineate emerging therapeutic strategies designed to dismantle this metabolic fortress. By targeting the "Achilles' heel" of mitochondrial dependency, disrupting the physical infrastructure of organelle hijacking, and revitalizing immunometabolism, we propose a multi-pronged framework to eradicate DTPs and prevent clinical relapse.
    Keywords:  drug-tolerant persisters (DTPs); immunometabolism; mitochondrial hijacking; oxidative phosphorylation; reverse Warburg effect; tumor metabolism
    DOI:  https://doi.org/10.7150/thno.131708
  5. Blood Neoplasia. 2026 May;3(2): 100202
    Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.
    Yoke Seng Lee, Jonathan D Good, Noha Awais, Benjamin K Eschle, Maia S Lineberry, Jingting Lin, Mark Wunderlich, Jenna Thibodeau, Holly Edwards, Jessica L Teo, Sarah Bibeau, Morgan Wollman, George Karadimov, Nurefsan Sariipek, Basit Salik, Jean Acosta, Jenny Noel, David G J Cucchi, Erica A K DePasquale, Prafulla C Gokhale, Jerome Ritz, Yubin Ge, Peter G Miller, Fadi J Najm, Richard M Stone, Jacqueline S Garcia, Andrew A Lane, Courtney L Jones, Peter van Galen.
      Targeted therapies, such as the BCL-2 inhibitor venetoclax, have expanded the treatment options for patients with acute myeloid leukemia (AML), but survival remains poor because of drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex messenger RNA structures in the 5' untranslated region (UTR) of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells relative to healthy hematopoietic stem and progenitor cells. Inhibition of eukaryotic initiation factor 4A (eIF4A) with the first-in-class small molecule zotatifin reduces the translation efficiency of transcripts related to the cell cycle and oncogenic signaling via the PI3K/AKT/mTOR pathway, as shown by ribosome profiling and gene set enrichment analysis. Western blot analysis corroborated these findings and demonstrated the downregulation of AKT, STAT-5, and MCL-1, factors implicated in resistance to venetoclax-based regimens. The combination of zotatifin and venetoclax synergistically kills AML cells in vitro and induces apoptosis across AML genotypes with selectivity toward progenitor-like cells in primary AML bone marrow (BM); however, its effect in primary healthy BM is limited. Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of zotatifin and venetoclax in relapsed/refractory disease.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100202
  6. Nat Commun. 2026 Mar 13.
    Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
    Michel Kahi, Abigail Mazzu, Ludovic Batistic, Marc Pujalte-Martin, Victor Tiroille, Anne Vincent, Joseph Murdaca, Loic Trapani, Paraskevi Kousteridou, Oumayma Benaceur, Amine Belaid, Marie Irondelle, Emilie Thomas, Christelle Boscagli, Pierre Bertrand, Heather S Carr, Frédéric Larbret, Emilie Baudelet, Stéphane Audebert, Didier F Pisani, Silvère Baron, Luc Camoin, Mathieu Carlier, Matthieu Durand, Damien Ambrosetti, Yu Chen, Jean-Jacques Diaz, Arnaud Jacquel, Issam Ben-Sahra, Nathalie M Mazure, Pascal Peraldi, Frédéric Bost.
      Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5Ahyp) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5Ahyp controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5Ahyp regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5Ahyp. Together, we uncover a critical role for eIF5Ahyp in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-70566-1
  7. Cell. 2026 Mar 06. pii: S0092-8674(26)00169-8. [Epub ahead of print]
    β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
    Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N Xu, Alberto Carturan, Chaoting Zhou, Kevin R Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Federico Stella, Andrew Lee, Siena Nason, Xianxin Hua, Michael Schneider, Madeleine Sleeman, Yunlin Zhang, Giulia Gabrielli, Ziqi Yang, Raymone Pajarillo, Ruchi Patel, Guido Ghilardi, Vrutti Patel, Akshita Joshi, Shunzhou Jiang, Yanqing Jiang, Patrizia Porazzi, Julia C Tchou, Brian Keith, Mingyao Li, Elise Chong, Stephen J Schuster, Michael Milone, Joshua Rabinowitz, Roddy S O'Connor, Christoph A Thaiss, Maayan Levy, Marco Ruella.
      The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.
    Keywords:  CAR T cell; cancer therapy; ketogenic diet; metabolism; oxidative phosphorylation; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.cell.2026.02.004
  8. BMB Rep. 2026 Mar 09. pii: 6743. [Epub ahead of print]
    Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
    Myeongwoo Jung, Seongho Cha, Eun Kyung Lee.
      Cellular senescence is an irreversible program of cell-cycle arrest that accumulates with age, contributing to chronic inflammation and various age-related diseases. A key feature of senescence paradigms is mitochondrial dysfunction, which involves not just a single defect but a series of coordinated changes in bioenergetics, redox homeostasis, mitochondrial quality control, and organelle interaction. Senescent cells often display a "quantity-quality imbalance" in their mitochondria: while the mitochondrial mass may increase, their efficiency in oxidative phosphorylation decreases, leading to a destabilized membrane potential (ΔΨm) and elevated levels of mitochondrial reactive oxygen species (mtROS). These interrelated changes can exacerbate senescence through persistent stress signaling, impaired turnover of damaged mitochondrial components, and alterations in organelle contacts, such as those between endoplasmic reticulum (ER) and mitochondria, and between mitochondria and lysosomes. Given that these phenotypes differ depending on cell type, triggering factors, and timing, no single assay can adequately define senescence-associated mitochondrial dysfunction. In this review, we present practical, complementary strategies that include extracellular flux-based respiration profiling, ATP output measurement, ΔΨm and ROS assessments, flux-based mitophagy reporters, quantitative network imaging, and contact-site assays. We propose minimal assay bundles that allow for a thorough multidimensional analysis. By establishing standardized, orthogonal measures of mitochondrial quantity and quality, we aim to enhance mechanistic understanding and facilitate the rational evaluation of mitochondria-targeted senolytic and senomorphic therapies.
  9. Nature. 2026 Mar 11.
    Ageing promotes metastasis via activation of the integrated stress response.
    Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.
      Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10216-0
  10. Curr Probl Cancer. 2026 Mar 11. pii: S0147-0272(26)00029-2. [Epub ahead of print]62 101295
    Immune-metabolic plasticity in AML: Prognostic roles of aCTLs (activated Cytotoxic T Cells) and Kynurenine.
    Amit Choudhary, Ramya Ramesh, Rakhee Kar, Prakash Babu Narasimhan, Prasanth Ganesan, Biswajit Dubashi, Rajesh Ng, Soundravally R, Smita Kayal.
      Acute myeloid leukemia (AML), traditionally risk-stratified by genetic abnormalities, is an aggressive malignancy with high relapse and modest survival. Immune dysregulation is an emerging pathogenic mechanism. We investigated cellular immune subsets and metabolic mediators of the PD-L1/PD-1 and IDO1-kynurenine-AhR pathways, including vitamin D as an immunomodulatory component in 78 newly diagnosed adult AML uniformly treated with intensive therapy. Lower TLC (<30 × 109/L) and blast percentage (<67%) were associated with higher CR rates (OR=3.9, p = 0.006; OR=2.9, p = 0.025). Higher baseline activated cytotoxic-T-cells (aCTLs; CD8+ PLCγ1+) predicted better OS (18-month OS 60.9% vs. 32.2%; p = 0.023). Other baseline clinical, vitamin D, and immune parameters were not associated with OS or LFS. Post-induction, kynurenine and Treg/CTL ratio increased, while tryptophan, aCTLs, and aTreg/aCTL ratio decreased. Higher post-treatment kynurenine was associated with better OS (30% vs. 64%; p = 0.017) and LFS (44% vs. 71%; p = 0.09). These findings highlight complex, plastic immune interactions in AML with potential prognostic and therapeutic implications. Micro-abstract: This study in de novo acute myeloid leukemia (AML) demonstrates that higher baseline activated cytotoxic T cells (CD8+PLCγ1+) and increased post-induction kynurenine are novel prognostic markers associated with improved survival after intensive chemotherapy. Chemotherapeutic treatment induces dynamic immune-metabolic changes, underscoring the importance of integrating immune profiling into clinical AML management.
    Keywords:  Acute myeloid leukemia; Clinical Outcomes; Cytotoxic T cell; Immune metabolic markers; Kynurenine; Post-chemotherapy
    DOI:  https://doi.org/10.1016/j.currproblcancer.2026.101295
  11. Nat Commun. 2026 Mar 13.
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Cristina Vázquez-Muñoz, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. Here, to investigate strategies that alleviate mitochondrial dysfunction, we first generate a ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfamfl/flUbcCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-chain fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share insufficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity, extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-70547-4
  12. Cancers (Basel). 2026 Mar 05. pii: 841. [Epub ahead of print]18(5):
    Addition of Venetoclax to Azacitidine Did Not Improve Survival in Acute Myeloid Leukemia and Was Not Well Tolerated: Real World Experience.
    David Yanni, Nupur Krishnan, Rouslan Kotchetkov.
      Introduction: Front-line therapy with Azacitidine (AZA) + Venetoclax (Ven) improved overall survival (OS) and remissions in acute myeloid leukemia (AML) patients ineligible for standard induction. Less is known about the outcome of AML treated with AZA + Ven in the "real world". Methods: We assessed the comparative pattern of administration, tolerability, efficacy and safety of AZA vs. AZA + Ven administered at our cancer centre. We retrospectively reviewed all patients treated with AZA alone or AZA + Ven. Patients who received less than one cycle or proceeded with consolidative stem cell transplant were excluded. Results: A total of 53 patients, median age 77 years, received AZA, and 23 patients, median age 73 years, received AZA + Ven. Among those, 69% and 47.8% were ≥75 years old, respectively. Only 52% received Ven doses above 200 mg. Mean time on therapy was 13.1 months in AZA vs. 5.9 months in AZA + Ven. Treatment delays occurred in 22.6% of AZA and 34.8% of AZA + Ven patients, primarily due to infections and cytopenias. Neutropenia grade 3/4 occurred in 28.3% of AZA vs. 56.5% of AZA + Ven patients. Thrombocytopenia grade 3/4 occurred in 15.1% of AZA and 51.2% of AZA + Ven patients. Anemia grade 3/4 occurred in 5.7% of AZA vs. 30.4% of AZA + Ven patients. Moreover, 69.8% of AZA and 69.5% AZA + Ven patients reached stable disease/partial and complete remission. Median overall survival (OS) was similar: 18 months in AZA vs. 14 months in the AZA + Ven group, p = 0.905. Conclusions: In a community setting, the addition of Venetoclax to AZA did not improve overall survival or disease control, mainly due to low tolerability and higher toxicity. However, these results should be interpreted cautiously due to a significant imbalance in the cytogenetic risk profiles and lower tolerability in the combined group. This suggests the need for a larger study with adjusted analyses.
    Keywords:  acute myeloid leukemia; azacitidine; efficacy; real world; safety; venetoclax
    DOI:  https://doi.org/10.3390/cancers18050841
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