bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–03–15
53 papers selected by
Christian Frezza, Universität zu Köln
  1. Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
  2. Gut microbiome-produced bile acid metabolite lengthens the circadian period in host intestinal cells.
  3. VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING.
  4. Enterocytes rely on purine biosynthesis/salvage pathway to facilitate dietary fat absorption.
  5. Heme as a metabolic cell-fate switch.
  6. Ageing promotes metastasis via activation of the integrated stress response.
  7. Targeting metabolism to combat anticancer and antibacterial drug resistance.
  8. β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
  9. Toward a consensus on the tumor microbiota: Evidence, standards, and interpretation.
  10. Of rigor and outreach, and practicing what we teach.
  11. Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
  12. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  13. Metabolic vulnerability in fusion-driven ependymoma.
  14. Reduced levels of mitochondrial ribosomal protein MRPL54 does not alter Apc related adenoma formation.
  15. Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis.
  16. Single-cell analyses identify independent aging processes that compete to determine cellular fate in budding yeast.
  17. USP7 facilitates brain tumor survival upon glucose deprivation by regulating phosphofructokinase muscle-type nuclear translocation in mice.
  18. Mutations and selection in normal tissues after cancer treatment.
  19. Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.
  20. ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.
  21. Post-Translational Regulation of CD8+ T Cell Fate and Dysfunction in Tumor Immunity.
  22. Fat bolsters tumours against ferroptosis.
  23. Defining the vascular niche of human adipose tissue across metabolic states.
  24. Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
  25. Lipid-dependent accrual of a subset of monocyte-derived macrophages is essential for tissue regeneration.
  26. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  27. Pareto optimality reveals an atlas of cellular archetypes.
  28. Emerging mechanisms of genome degradation during the mtDNA life cycle.
  29. Angiocrine breakdown in metabolically stressed fat.
  30. The Yin-Yang balance of SIRT1 and SIRT2 in cancer metabolic remodeling.
  31. Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
  32. Degradation of the Molecular Basis of Life During the Aging Process.
  33. Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer.
  34. In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
  35. Circadian reprogramming by timed sodium intake reveals transcriptional pathways of daily salt handling in the colon.
  36. Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
  37. Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.
  38. A druggable redox switch on SHP1 controls macrophage inflammation.
  39. p38 MAPK orchestrates cross-tissue potassium homeostasis for survival.
  40. Intestinal interoceptive dysfunction drives age-associated cognitive decline.
  41. Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility.
  42. Dual phagocytosis-checkpoint blockade revitalizes immune surveillance in mouse models of glioblastoma.
  43. How somatic evolution affects health.
  44. Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
  45. 'Virtual cell' captures the most-basic process of life: bacterial division.
  46. Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control.
  47. Heterogeneity in lysosomal dynamics and metabolic functions along the kidney proximal tubule.
  48. Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.
  49. Lifelong behavioral screen reveals an architecture of vertebrate aging.
  50. Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer.
  51. SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington's disease models.
  52. Communication breakdown: senescent cells in interorgan communication of aging.
  53. Simultaneous spatial transcriptomics and morphology profiling as tools to explore how microglia change with age.
  1. Nat Cell Biol. 2026 Mar 13.
    Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
    Vera Skafar, Izadora de Souza, Biplab Ghosh, Ancely Ferreira Dos Santos, Florencio Porto Freitas, Zhiyi Chen, Shibo Sun, Merce Donate Castillo, Palina Nepachalovich, Lars Seufert, Sebastian Bothe, Juliane Tschuck, Apoorva Mathur, Ariane Nunes-Alves, Jannik Buhr, Camilo Aponte-Santamaría, Werner Schmitz, Matthias Mack, Martin Eilers, Ralf Bargou, Milena Chaufan, Mayher Kaur, Mario Palma, Jessalyn M Ubellacker, Ulrich Elling, Hellmut G Augustin, Kamyar Hadian, Svenja Meierjohann, Bettina Proneth, Marcus Conrad, Maria Fedorova, Hamed Alborzinia, José Pedro Friedmann Angeli.
      Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.
    DOI:  https://doi.org/10.1038/s41556-025-01856-x
  2. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2506313123
    Gut microbiome-produced bile acid metabolite lengthens the circadian period in host intestinal cells.
    Chelsea E Powell, Alana M McSween, Lenka Dohnalová, Cecilia H Kim, Robyn J Eisert, Zhen-Yu J Sun, Hyuk-Soo Seo, Vincent Marquardt, Sirano Dhe-Paganon, Christoph A Thaiss, A Sloan Devlin.
      Host circadian signaling, feeding, and the gut microbiome are tightly interconnected. Changes in the gut microbial community can affect the expression of core clock genes, but the specific metabolites and molecular mechanisms that mediate this relationship remain largely unknown. Here, we sought to identify gut microbial metabolites that impact circadian signaling. Through a phenotypic screen of a focused library of gut microbial metabolites, we identified a bile acid metabolite, lithocholic acid (LCA), as a circadian modulator. LCA lengthened the circadian period of core clock gene hPer2 transcription in a dose-responsive manner in human colonic cells. We found evidence that LCA modulates the casein kinase 1 δ/ε (CK1δ/ε)-protein phosphatase 1 (PP1) feedback loop and stabilizes core clock protein cryptochrome 2 (CRY2). Furthermore, we showed that LCA feeding alters circadian transcription in mouse distal ileum and colon. Taken together, our work identifies LCA as a molecular link between host circadian biology and the microbiome. Because bile acids are secreted in response to feeding, our work provides potential mechanistic insight into the molecular nature of the food-entrainable oscillator (FEO) by which peripheral clocks adapt to the timing of food intake. Given the association between circadian rhythm, feeding, and metabolic disease, our insights may offer an avenue for modulating host health.
    Keywords:  bile acids; circadian rhythm; microbiome
    DOI:  https://doi.org/10.1073/pnas.2506313123
  3. Nat Commun. 2026 Mar 12.
    VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING.
    James A C Bertlin, Tekle Pauzaite, Qian Liang, Niek Wit, James C Williamson, Jia Jhing Sia, Nicholas J Matheson, Brian M Ortmann, Thomas J Mitchell, Anneliese O Speak, Qing Zhang, James A Nathan.
      Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in VHL-null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.
    DOI:  https://doi.org/10.1038/s41467-026-70517-w
  4. Nat Commun. 2026 Mar 13.
    Enterocytes rely on purine biosynthesis/salvage pathway to facilitate dietary fat absorption.
    Yu Wang, Li Chen, Yingze Ma, Mingqi Zhou, Aleksander Geske, Marcus Seldin, Jiangjiang Zhu, Alexander M Zak, Xinzhong Dong, Robert N Cole, Svetlana Lutsenko.
      Dietary fat absorption is among the most energy-demanding processes of nutrient uptake. Fatty acid activation, triglyceride synthesis, and the trafficking of chylomicrons through the secretory pathway - all require ATP. How enterocytes accommodate the surge in ATP consumption following fat uptake is unclear. We show that the purine biosynthesis/salvage pathway supplies necessary ATP and that Ankyrin Repeat Domain 9 (ANKRD9) couples ATP synthesis and lipoprotein trafficking. Ankrd9 regulates enzymes within the purine biosynthesis pathway to increase ATP synthesis and facilitate Golgi dynamics. Intracellular localization of ANKRD9 is lipid and ATP-dependent. Inactivation of Ankrd9 in mice reduces intestinal ATP despite intact mitochondrial and glycolytic function, alters Golgi morphology, delays ApoB/chylomicron trafficking, and causes lipid accumulation in enterocytes, along with a lean body phenotype. Taken together, the results reveal a previously unrecognized mechanism that regulates lipid absorption in enterocytes and identify ANKRD9 as a central component of this mechanism.
    DOI:  https://doi.org/10.1038/s41467-026-70332-3
  5. Trends Endocrinol Metab. 2026 Mar 10. pii: S1043-2760(26)00033-0. [Epub ahead of print]
    Heme as a metabolic cell-fate switch.
    Jia Liu, Rui Kang, Daolin Tang.
      Heme availability shapes mitochondrial function, redox balance, and innate immune signaling. Recent studies reveal threshold-dependent heme states that predispose cells to cuproptosis, ferroptosis, apoptosis, pyroptosis, or PANoptosis. Viewing heme as a metabolic rheostat provides a unifying framework for interpreting regulated cell death across cancer, infection, and metabolic disease.
    Keywords:  damage-associated molecular pattern signaling; heme metabolism; immunometabolism; mitochondrial stress; regulated cell death
    DOI:  https://doi.org/10.1016/j.tem.2026.01.017
  6. 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
  7. Trends Pharmacol Sci. 2026 Mar 11. pii: S0165-6147(26)00017-9. [Epub ahead of print]
    Targeting metabolism to combat anticancer and antibacterial drug resistance.
    Carolina H Chung, Rupa Bhowmick, Annie J Badenoch, Harkirat S Arora, Sriram Chandrasekaran.
      Drug resistance is a major challenge in cancer and infectious diseases, requiring innovative solutions. Recent research suggests that bacteria and cancer cells reprogram their metabolism and manipulate their external metabolic environment to resist a diverse range of therapeutics. Emerging technologies, including single-cell and spatial omics profiling, CRISPR chemogenomics, machine learning, and metabolic network modeling, have revealed the metabolic complexities within bacterial biofilms, tuberculosis granulomas, and the tumor microenvironment. Here, we examine metabolic mechanisms that aid drug resistance across these different disease areas; this includes activation of antioxidant defenses, manipulation of the host immune response, and rewiring of energy metabolism. This analysis of shared metabolic factors across diseases may inspire repurposing of drugs, immunotherapies, and dietary interventions to overcome resistance.
    Keywords:  bacterial infections; cancer; cell metabolism; drug repurposing; drug resistance; systems biology
    DOI:  https://doi.org/10.1016/j.tips.2026.01.013
  8. 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
  9. Cancer Cell. 2026 Mar 12. pii: S1535-6108(26)00109-1. [Epub ahead of print]
    Toward a consensus on the tumor microbiota: Evidence, standards, and interpretation.
    Tingting Duan, Aviel Rosenbaum, Vidhi Chandra, Luca Tiraboschi, Maria Rescigno, Florencia McAllister, Ravid Straussman, Marlies Meisel.
      Tumors across diverse organs harbor microbial communities that can shape cancer biology and therapeutic responses, yet the field remains polarized by technical and interpretive challenges. In this commentary, we synthesize functional and mechanistic evidence linking intratumoral microbes to cancer hallmarks; critically evaluate current detection approaches; and propose minimal technical and reporting standards to establish microbial presence, viability, and causality. We highlight common pitfalls and outline priorities to move the tumor microbiota field toward robust, clinically actionable insights.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.011
  10. Nat Cell Biol. 2026 Mar 13.
    Of rigor and outreach, and practicing what we teach.
    Melina Casadio, Aditi U Gurkar.
      
    DOI:  https://doi.org/10.1038/s41556-026-01914-y
  11. 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
  12. Nat Struct Mol Biol. 2026 Mar 13.
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Colin J Delaney, Amr Al-Farhan, Alyssa J Mathiowetz, Cody E Doubravsky, Derek A Pratt, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1-FAD binding triggered FSP1 degradation through a ubiquitin-proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1038/s41594-026-01759-x
  13. Nat Rev Cancer. 2026 Mar 12.
    Metabolic vulnerability in fusion-driven ependymoma.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-026-00920-4
  14. PLoS One. 2026 ;21(3): e0344161
    Reduced levels of mitochondrial ribosomal protein MRPL54 does not alter Apc related adenoma formation.
    Claudia N Spaan, Eileen Daniels, Wouter L Smit, Ruben J de Boer, Joana Silva, Jacqueline L M Vermeulen, S Meisner, Vanesa Muncan, Riekelt H Houtkooper, Jarom Heijmans.
      Reprogramming of energy metabolism is one of the hallmarks of cancer cells and mutations that modify wild type intestinal cells to colon carcinomas increases cellular energy expenditure. Mitochondria are the main site for ATP production in (cancer) cells and disrupting their function results in impaired tumor forming efficacy. The mitochondrial ribosomal proteins (MRPs) constitute the ribosome specifically in mitochondria, and as such are crucial for the translation process of the electron transport chain complex subunits. We hence aimed to explore the consequence of reduced MRP expression on adenomagensis and investigate this in a genetic mouse model with bodywide heterozygosity for Mrpl54. We show that Mrpl54 heterozygosity does not alter adenoma formation, intestinal proliferation or apoptosis in a heterozygous Apc model. Furthermore, diminished Mrpl54 expression did not decrease stemness or global parameters of metabolism in colorectal cancer cell lines.
    DOI:  https://doi.org/10.1371/journal.pone.0344161
  15. Sci Adv. 2026 Mar 13. 12(11): eaeb1611
    Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis.
    Bruno Beernaert, Rose L Jady-Clark, Parin Shah, Erik Ramon-Gil, Nora M Lawson, Zack D Brodtman, Somnath Tagore, Frederik Stihler, Alfie S Carter, Shannique Clarke, Tong Liu, Winston M Zhu, Juliet E Martin, Erkin Erdal, Alistair Easton, Leticia Campo, Molly Browne, Stephen Ash, Rabial Q Raja, Nicola Waddell, Tom Crosby, Simon R Lord, Derek A Mann, Ignacio Melero, Carlos E de Andrea, Andréa E Tijhuis, Floris Foijer, Ester M Hammond, Kadir C Akdemir, Jack Leslie, Benjamin Izar, Eileen E Parkes.
      Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS-STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS-STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines-with CXCL8 as a prominent hit-as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell-mediated immunosuppression. In patients with EAC, CINhigh, myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS-STING signaling. These insights explain the counterintuitive maintenance of cGAS-STING and highlight the disruption of the CIN-cGAS-inflammation axis as a potential therapeutic strategy in EAC.
    DOI:  https://doi.org/10.1126/sciadv.aeb1611
  16. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2534452123
    Single-cell analyses identify independent aging processes that compete to determine cellular fate in budding yeast.
    Manuel Hotz, Rachel G Kroll-Ling, Nathaniel H Thayer, Daniel E Gottschling.
      Phenotypic heterogeneity is prevalent during aging, yet its underlying molecular drivers remain poorly understood. In budding yeast, two distinct aging trajectories, characterized by either ribosomal DNA (rDNA) instability or mitochondrial decline, have been proposed to be mutually exclusive. Here, we systematically dissect the heterogeneity among aging yeast cells by combining single-cell transcriptomics with longitudinal fluorescence microscopy. Our data reveal distinct transcriptional responses that emerge in aging cells, highlighted by loss of rDNA silencing, a hypoxia response, and the environmental stress response (ESR). Contrary to expectation, we establish that ESR induction is not caused by rDNA instability but is instead a consequence of an early decline in mitochondrial membrane potential. However, the ESR is merely a biomarker of this decline and not itself a determinant of lifespan. While rDNA instability and mitochondrial dysfunction are anticorrelated as terminal phenotypes, we find that they are not necessarily mutually exclusive and can instead proceed concurrently within individual cells. Targeted genetic perturbations that are specific for one pathway do not impinge on the other, which is in contradiction to the idea of mutual inhibition between the two. We therefore propose a "competing hazards model", where independent aging processes progress in parallel, and the observed mode of death is determined by which process first reaches a catastrophic failure point. Our work untangles the causal links between several aging pathways and provides a framework for understanding how distinct aging trajectories emerge from independent molecular events.
    Keywords:  aging; mitochondria; phenotypic heterogeneity; single-cell RNA seq; yeast
    DOI:  https://doi.org/10.1073/pnas.2534452123
  17. PLoS Biol. 2026 Mar;24(3): e3003698
    USP7 facilitates brain tumor survival upon glucose deprivation by regulating phosphofructokinase muscle-type nuclear translocation in mice.
    Siyang Wu, Ruixiu Cao, Xiaolan Huang, Qiongni Feng, Yajuan Zhang, Hong Gao, Bangbao Tao, Ji Liang, Weiwei Yang.
      Cancer cells reprogram the metabolic pathways to adapt to nutrient deficiency, while the underlying mechanism has not been fully understood. Phosphofructokinase 1 muscle type (PFKM) is the second rate-limiting step of glycolysis, catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. Here we show, using an orthotopic xenograft glioma mouse model, that PFKM is deubiquitinated and translocated into nucleus upon glucose deficiency, thereby activating fatty acid oxidation (FAO), which sustains tumor cell survival and ultimately promotes glioblastoma (GBM) development. Mechanistically, the levels of fructose-2,6-bisphosphate (F-2,6-BP) are decreased in tumor cells upon glucose deficiency, which enhances the interaction between ubiquitin carboxyl-terminal hydrolase 7 (USP7) and PFKM. USP7 removes the monoubiquitination of PFKM at lysine (K) 615, thereby promoting PFKM's translocation into the nucleus. Nuclear PFKM interacts with c-MYC, which upregulates the expression of carnitine o-palmitoyltransferase 1 muscle isoform (CPT1B) to activate FAO, thereby sustaining tumor cell survival upon glucose deficiency. Notably, USP7 inhibitor effectively dampens GBM development and extends the survival duration of the mice. The levels of nuclear PFKM correlate with the malignancy and prognosis of human GBM patients. Our findings reveal a novel mechanism through which USP7 senses fructose-2,6-bisphosphate levels to promote PFKM nuclear translocation, thereby sustaining tumor cell survival under nutrient deficiency by activating FAO. This establishes the critical role of USP7 in brain tumor development and suggests the therapeutic potential of USP7 inhibitors for treating GBM.
    DOI:  https://doi.org/10.1371/journal.pbio.3003698
  18. Nat Genet. 2026 Mar;58(3): 472
    Mutations and selection in normal tissues after cancer treatment.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-026-02557-3
  19. Cell Metab. 2026 Mar 10. pii: S1550-4131(26)00051-3. [Epub ahead of print]
    Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.
    Snigdha Tiash, Saket Awadhesbhai Patel, Marjori Russo, Anusha Suresh, Bo Pang, Yun-Ling Pai, Wentong Jia, Rachael L Field, Terri Pietka, Nada A Abumrad, Gordon I Smith, Dmitri Samovski, Samuel Klein, Jonathan R Brestoff, Clair Crewe.
      Extracellular vesicles (EVs) are now recognized as potent mediators of inter-organ signaling and are implicated in the pathogenesis of obesity and associated comorbidities. Despite a recent surge in functional information about EVs, we still lack a basic understanding of how endogenous EV levels are controlled to regulate inter-organ signaling. New flow cytometry technologies have allowed us to study the regulation of circulating endogenous EVs from metabolically relevant cell types such as adipocytes (adipocyte-derived EVs [adipoEVs]). We provide evidence for a paradigm of EV regulation in which tissue-resident immune cells, predominantly macrophages, clear EVs released by local tissue cells or those entering the tissue from circulation, an activity that determines circulating EV levels. In obesity, EV uptake by adipose tissue immune cells is reduced, leading to increased circulating adipoEVs and reduced adipoEV clearance rates. This work shows that tissue immune cells gate tissue EV entry into the circulation, making them key regulators of inter-organ EV signaling.
    Keywords:  adipocyte; exosomes; extracellular vesicles; insulin resistance; inter-organ signaling; macrophage; mitochondria; obesity; spectral flow cytometry; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.008
  20. Cell Rep. 2026 Mar 06. pii: S2211-1247(26)00104-X. [Epub ahead of print]45(3): 117026
    ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.
    Heegwon Shin, Tyler J Dorrity, Justin Aruda, Kenenni A Wiegand, Jung Seung Nam, Jiping Yang, Aidan S Jones, Jake A Gertie, Meera K Singh, Yuanjun Yin, Keer He, Rafan Sarker, Rajesh K Soni, Yousin Suh, Iok In Christine Chio, Silvi Rouskin, Hachung Chung.
      Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.
    Keywords:  A-to-I editing; ADAR1; AGS; Aicardi-Goutieres syndrome; CP: immunology; CP: molecular biology; IFN; PKR; double-stranded RNA; dsRNA; dsRNA-seq; innate immunity; mitochondria; mitochondrial stress; protein kinase R; type 1 interferon
    DOI:  https://doi.org/10.1016/j.celrep.2026.117026
  21. Adv Sci (Weinh). 2026 Mar 12. e74807
    Post-Translational Regulation of CD8+ T Cell Fate and Dysfunction in Tumor Immunity.
    Zihao Zhou, Xu Chen, Nina Li, Meiyan Zou, Yunfan Lin, Pei Lin, Weiyao Feng, Xinyuan Zhao, Li Cui.
      CD8+ T cells are central executors of antitumor immunity, yet their activation, effector differentiation, and long-term persistence are governed by diverse post-translational modifications (PTMs). These chemical modifications function as rapid and reversible regulators that link antigenic stimulation, metabolic availability, and inflammatory cues to the transcriptional and chromatin programs that define CD8+ T cell fate. Core PTM classes-including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation-precisely tune signaling thresholds, cytotoxic commitment, and memory formation, while emerging metabolism-responsive modifications such as lactylation directly connect nutrient flux to functional fitness. In solid tumors, chronic antigen exposure, hypoxia, nutrient restriction, and lactate accumulation profoundly remodel these modification networks, stabilizing dysfunction-associated states, impairing metabolic flexibility, and diminishing cytotoxic capacity. This review integrates current mechanistic understanding of how major PTM pathways coordinate the lifecycle of CD8+ T cells-from initial activation to effector acquisition, memory establishment, dysfunction, and exhaustion. We further discuss how the tumor microenvironment reprograms PTM landscapes to reinforce dysfunction and promote immune escape. Finally, we highlight the challenges and future directions in deciphering and targeting PTMs in CD8+ T cells. Future efforts to manipulate PTMs hold significant potential to improve cancer immunotherapies by restoring the antitumor efficacy of CD8+ T cells within the tumor microenvironment.
    Keywords:  CD8+ T cell; PTMs; TME; metabolic regulation; tumor immunotherapy
    DOI:  https://doi.org/10.1002/advs.74807
  22. Nat Cell Biol. 2026 Mar 11.
    Fat bolsters tumours against ferroptosis.
    Eikan Mishima, Marcus Conrad.
      
    DOI:  https://doi.org/10.1038/s41556-026-01904-0
  23. Nat Metab. 2026 Mar 12.
    Defining the vascular niche of human adipose tissue across metabolic states.
    Ibrahim AlZaim, Mohamed N Hassan, Maja Schröter, Luca Mannino, Katarina Dragicevic, Marie Balle Sjogaard, Joseph Festa, Lolita Dokshokova, Sophie Weinbrenner, Blanca Tardajos Ayllon, Bettina Hansen, Rikke Kongsgaard Rasmussen, Julie N Christensen, Olivia Wagman, Ruby Schipper, Min Cai, Wouter Dheedene, Anja Bille Bohn, Jean Farup, Lin Lin, Samuele Soraggi, Anna Dalsgaard Thorsen, Amanda Bæk, Henrik Holm Thomsen, Maximilian von Heesen, Lena-Christin Conradi, Paul Evans, Carolina E Hagberg, Joerg Heeren, Margo Emont, Evan D Rosen, Aernout Luttun, Anders Etzerodt, Lucas Massier, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Konstantin Khodosevich, Robert A Fenton, Bilal N Sheikh, Niels Jessen, Laura P M H de Rooij, Joanna Kalucka.
      Adipose tissue homeostasis depends on an intact vascular network that ensures adequate nutrient delivery and immune regulation. In obesity, vascular dysfunction, particularly within endothelial cells (ECs), contributes to inflammation and metabolic disease progression, yet the cellular organization of the human adipose vasculature remains poorly defined. Here we show, using single-cell RNA sequencing of nearly 70,000 vascular cells from human subcutaneous adipose tissue of 65 individuals, that the adipose vasculature is highly heterogeneous and consists of seven canonical EC subtypes. In addition, we identify a distinct population of ECs that display mixed endothelial, mesenchymal, adipocytic and immune transcriptional features. Computational analyses and whole-mount imaging support their presence and suggest that they emerge through endothelial-to-mesenchymal transition. Comparative analyses further reveal inflammatory and fibrotic vascular signatures in obesity and type 2 diabetes. Together, this atlas delineates the cellular complexity of the human adipose vasculature and highlights its contribution to metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-026-01475-2
  24. J Biol Chem. 2026 Mar 10. pii: S0021-9258(26)00227-9. [Epub ahead of print] 111357
    Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
    Varun Ponnusamy, Deahzana R Randall, Zheng Hong Lee, Nupur K Das, Liang Zhao, Kathryn Buscher, Sumeet Solanki, Adam R Renslo, Peggy P Hsu, Yatrik M Shah.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the elevated iron must be counterbalanced given its potential to generate damaging reactive oxygen species. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. Selenoenzyme glutathione peroxidase 4 (GPX4) controls this process by reducing lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined and whether ferroptosis is accompanied by dynamic changes in the LIP is unknown. To examine this, we treated CRC cells with exogenous iron and pharmacologic ferroptosis inducers. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, by assessing expression of iron regulatory genes as well as employing two orthogonal approaches to measure labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 or SLC7A11 inhibition. These findings suggest that the LIP does not expand upon pharmacologically initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.
    Keywords:  Cell Death; Colon Cancer; Iron; Lipid Peroxidation; Metabolic Regulation; Metal Homeostasis; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.jbc.2026.111357
  25. Nat Metab. 2026 Mar 11.
    Lipid-dependent accrual of a subset of monocyte-derived macrophages is essential for tissue regeneration.
    Tao Yao, Xin Tian, Linbin Rao, Jinling Ni, Jiayong Yu, Hongguo Yang, Yuexiao Tang, Xingxiao Huang, Xintong Xia, Lin Zhao, Bowen Diao, Yan Ping, Danni Wei, Siqi Li, Hui Chai, Zhiming Hu, Xiongzhong Ruan, Suihan Feng, Mengle Shao, Bo Shan, Ying Wu.
      Tissue regeneration is essential for maintaining tissue homoeostasis and influences disease progression. In the liver, injury evokes a complex regenerative response with robust immune activation and metabolic rewiring, yet how these processes coordinate hepatocyte proliferation remains unclear. Here we show the presence of an injury-induced, lipid-dependent accrual of a distinct monocyte-derived macrophage (MDM) subset characterized by abundant cytosolic lipid content and heightened inflammatory response. Multi-omic analyses, spanning both single-cell transcriptomics and quantitative lipidomics, unveil substantial cellular diversity and heterogeneity between these 'lipo-inflammatory MDMs' (termed LIMMs) and other hepatic macrophages, including Kupffer cells. Blocking CD36-dependent LIMM induction markedly impairs hepatocyte proliferation and liver regeneration in injured livers. Mechanistically, CD36-mediated increase in ceramide biosynthesis activates IRE1α-XBP1 signalling pathway in LIMMs, driving production of the regenerative cytokine interleukin-6. Disrupting CD36-dependent IRE1α activation in LIMMs compromises liver repair. These findings identify a lipid-laden MDM subcluster as a key regulator of regenerative inflammation in injured livers.
    DOI:  https://doi.org/10.1038/s42255-026-01480-5
  26. 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
  27. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2530194123
    Pareto optimality reveals an atlas of cellular archetypes.
    George Crowley, Uri Alon, Stephen R Quake.
      We sought to identify universal organizing principles behind phenotypic variation within cell types. Pareto optimality describes how trade-offs between optimal solutions account for variation, predicting that the boundary points of a data distribution reflect specialized functions. We hypothesized that transcriptomic variation was explained by Pareto optimality across all cell types. We then used the Tabula Sapiens Atlas of single-cell RNA sequencing across cell types and tissues in the human body to test this hypothesis and found that most cell types adhere to this theory. This enabled us to use this principled method to characterize the functions performed by each cell type. These phenotypes are derived from an unbiased approach and do not incorporate ideas from existing biological models or theories, and yet in many cases they recapitulate our understanding of the functions of major cell types. Ultimately, we conclude that multiobjective optimization broadly shapes the observed phenotypic variation within cell types. This finding enables us to write explicit representations of the low-dimensional manifolds on which transcriptomes of single cells reside. This can inform the design of the next generation of virtual cell language models, which aim to statistically learn low-dimensional transcriptomic manifolds.
    Keywords:  biophysics; cell biology; computational biology
    DOI:  https://doi.org/10.1073/pnas.2530194123
  28. Nat Cell Biol. 2026 Mar 13.
    Emerging mechanisms of genome degradation during the mtDNA life cycle.
    Luis Carlos Tábara, Julien Prudent.
      
    DOI:  https://doi.org/10.1038/s41556-026-01903-1
  29. Nat Metab. 2026 Mar 12.
    Angiocrine breakdown in metabolically stressed fat.
    Shannon M Reilly, Yang Lin, Shahin Rafii.
      
    DOI:  https://doi.org/10.1038/s42255-026-01481-4
  30. Int J Biol Sci. 2026 ;22(5): 2702-2719
    The Yin-Yang balance of SIRT1 and SIRT2 in cancer metabolic remodeling.
    Fei Yi, Li Shen, Xindi Yang, Zhuo Wang, Xue Li, Zishi Shen, Wenting Liu, Qi Miao, Shuang Jiang, Eryan Kong, Xiaoyu Song, Tingting Zhou, Ning Bai, Liu Cao.
      Sirtuin 1 (SIRT1) and Sirtuin 2 (SIRT2) are NAD⁺-dependent deacetylases that regulate cancer metabolic stress, exerting their effects primarily through post-translational modification of metabolic enzymes and transcription factors. They modulate glucose, lipid, and mitochondrial metabolism, as well as immune metabolism responses within the tumor microenvironment. Depending on cellular context, they can promote or suppress tumor growth by directing energy production, redox balance, and metabolic adaptation. These context-dependent and often opposing activities constitute a Yin-Yang mode of regulation in cancer metabolism, reflecting a dynamic balance between metabolic activation and constraint. Autophagy has emerged as a critical metabolic integration node regulated by both SIRT1 and SIRT2, linking nutrient sensing, mitochondrial quality control, and stress adaptation. This review summarizes recent advances in understanding how SIRT1 and SIRT2 coordinate tumor metabolism and discusses therapeutic strategies that target their regulatory balance to reprogram cancer metabolism. SIRT2 also functions as a metabolic checkpoint that restrains CD8⁺ T cell effector metabolism, providing a rationale for combining SIRT2 inhibition with immune checkpoint blockade in metabolically stressed tumor microenvironments.
    Keywords:  SIRT1 and SIRT2; glucose metabolism; lipid metabolism; mitochondrial metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.7150/ijbs.127696
  31. Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00189-8. [Epub ahead of print] 218426
    Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
    Emma Martell, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Charul Jain, Christopher M Anderson, Tanveer Sharif.
      Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.
    Keywords:  Cancer metabolism; brain tumors; epigenetics; metabolic therapy; tumor signaling
    DOI:  https://doi.org/10.1016/j.canlet.2026.218426
  32. Int J Mol Sci. 2026 Mar 06. pii: 2419. [Epub ahead of print]27(5):
    Degradation of the Molecular Basis of Life During the Aging Process.
    Janusz Wiesław Błaszczyk.
      Aging is a chronic, destructive process characterized by the progressive breakdown of the body, leading to a loss of control over homeostasis. Glucose is the most important metabolite involved in metabolism and maintaining homeostasis in the human body. Glucose-based energy metabolism is fundamental to the activity and structural changes in the brain, which is the main regulator of life processes. Disturbances in energy metabolism and glucose-dependent metabolic processes have a decisive impact on the aging process. Age-related deficiency of the coenzyme NAD, which regulates glucose metabolism in neurons, leads to irreversible changes in the brain, culminating in senescence. Research on NAD precursors offers hope that although we cannot completely halt the aging process, NAD supplementation may enable healthy aging.
    Keywords:  NAD; aging; energy metabolism; glycolysis; life; morphogenesis
    DOI:  https://doi.org/10.3390/ijms27052419
  33. 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
  34. PNAS Nexus. 2026 Mar;5(3): pgag027
    In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
    Victoria W D'Agostino, Michelle Kwan, Adelle Yong, Kira Grossman, Enakshi D Sunassee, Megan C Madonna, Matthew Hirschey, Gregory M Palmer, Nirmala Ramanujam.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and a high likelihood of recurrence. Residual disease after therapy is a key predictor of recurrence, often driven by intratumoral metabolic heterogeneity. Accumulating evidence indicates that tumors are able to shift between glycolysis and oxidative metabolism and alter nutrient preferences to sustain growth and resist therapy. We have developed a in vivo microscope that enables near-simultaneous measurements of fluorescent metabolic surrogates of glucose, fatty acids, and oxidative phosphorylation through a combination of spectral separation and sequential delivery schemes. Widefield imaging with uniform illumination across the entire tumor landscape (5 mm × 5 mm) informs on the spatial distribution of these metabolic probes. We used this technology to investigate metabolic heterogeneity of a murine model of TNBC (4T1 tumor line) and normal mammary tissues that have distinctly different metabolic pathways. Mammary tissues relied primarily on oxidative metabolism and showed high levels of glucose and fatty acid uptake across the entire imaging area reflecting a single metabolic phenotype. Though tumors were predominantly glycolytic, they displayed a heterogeneous distribution of nutrient preferences with regions dominated by either fatty acid uptake, glucose uptake, or both. Taken together, this work highlights the importance of not only capturing multiple metabolic endpoints but also investigating their spatial relationships to understand heterogeneity in key substrates and metabolic pathways for energy production in vivo.
    Keywords:  breast cancer; fatty acid oxidation; fluorescence microscopy; glycolysis; tumor metabolism
    DOI:  https://doi.org/10.1093/pnasnexus/pgag027
  35. Sci Adv. 2026 Mar 13. 12(11): eady9244
    Circadian reprogramming by timed sodium intake reveals transcriptional pathways of daily salt handling in the colon.
    Takuto Torimitsu, Kenichiro Kinouchi, Kousha Changizi Ashtiani, Sherif Abdelkarim, Tomoki Sato, Takahide Kozuma, Na Yao, Akihide Iwahara, Kyosuke Kato, Shun Tonomura, Toshifumi Nakamura, Kenichi Yokota, Isao Kurihara, Pierre Baldi, Hiroshi Itoh, Kaori Hayashi.
      Circadian misalignment of the feeding behavior and the terrestrial cycle is associated with obesity and metabolic perturbations. However, it remains unclear whether the quantity and timing of dietary salt intake influence temporal sodium handling and blood pressure regulation. Here, we demonstrate that the colonic mineralocorticoid receptor (MR) and peripheral clock affect the daily sodium absorption and blood pressure variations. Genes related to sodium handling display diurnal rhythms in synchrony with the daily rhythms of aldosterone and the colonic circadian clock. Cistromic analysis substantiated the overlap of occupancy between the MR and brain and muscle ARNT-like 1 (BMAL1). Diurnal oscillation of aldosterone and peripheral clocks, as well as blood pressure, was robustly driven by nighttime feeding of a low-salt diet but markedly disrupted by daytime feeding of a high-salt diet in nocturnal mice. These findings delineate the colonic temporal sensing of dietary sodium abundance and highlight the transcriptional mechanisms of daily salt handling and blood pressure variations.
    DOI:  https://doi.org/10.1126/sciadv.ady9244
  36. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]
    Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
    Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.
      Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.
    DOI:  https://doi.org/10.64898/2026.02.26.708335
  37. bioRxiv. 2026 Mar 01. pii: 2026.02.27.708635. [Epub ahead of print]
    Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.
    Yetiş Gültekin, Sharanya Sivanand, Kian M Eghbalian, Anna M Barbeau, Keene L Abbott, George Eng, Victoria L Tavernier, Brian T Do, Heaji Shin, Elif Özçelik, Sabrina Hu, Tenzin Kunchok, Millenia Waite, William M Rideout, Yiğit K Kizlier, Daniel A Sharygin, William A Freed-Pastor, Tyler Jacks, Eileen White, Ömer H Yilmaz, Jonathan A Nowak, Brian M Wolpin, Matthew G Vander Heiden.
      Normal pancreas function supports both digestion and the hormonal regulation of whole-body metabolism. We find pancreatic ductal adenocarcinoma (PDAC) disrupts the normal function of the remaining pancreas, leading to altered systemic metabolism and peripheral tissue wasting that begins early in disease progression. Using mouse models of PDAC, we find small pancreas tumors lead to both endocrine and exocrine pancreatic dysfunction that results in systemic nutrient depletion and loss of both muscle and fat tissue. Providing free glucose in the diet that is absorbed despite pancreatic exocrine dysfunction causes hyperglycemia and blunts fat wasting without affecting muscle loss. Muscle mass can be restored by free dietary amino acids or pancreatic enzyme supplementation. Exocrine dysfunction causing reduced dietary protein digestion promotes muscle proteolysis and autophagy. Autophagy is a major driver of muscle wasting in PDAC, as muscle-specific deletion of the core autophagy gene Atg7 also reduces muscle wasting. Disrupting muscle autophagy without restoring systemic nutrition slows tumor growth and improves survival of mice with PDAC. Tracing the fate of amino acids released from muscle of mice with PDAC shows redistribution to both tumor and host tissues. Notably, improving nutrition in mice with disrupted muscle autophagy promotes tumor growth. Together, the data argue that early peripheral tissue wasting associated with early pancreatic cancer is driven by altered normal pancreatic organ function that leads to reduced nutrition and enhanced muscle autophagy, releasing nutrients to support both tumor and host metabolism.
    DOI:  https://doi.org/10.64898/2026.02.27.708635
  38. Nat Chem Biol. 2026 Mar 12.
    A druggable redox switch on SHP1 controls macrophage inflammation.
    Mei Ying Ng, Meredith N Nix, Guangyan Du, Ivan Davidek, Nils Burger, Sanghee Shin, Sean Toenjes, Haruna Takeda, Megan Cheah Xin Yan, Bingsen Zhang, Haopeng Xiao, Shelley M Wei, Hyuk-Soo Seo, Sirano Dhe-Paganon, Thomas E Wales, John R Engen, Evanna L Mills, Jianwei Che, Tinghu Zhang, Nathanael S Gray, Edward T Chouchani.
      Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-026-02163-8
  39. Nat Commun. 2026 Mar 09.
    p38 MAPK orchestrates cross-tissue potassium homeostasis for survival.
    Rong Huang, Fangchao Hu, Yiyao Li, Qifei Gao, Jintao Huang, Jiarui Wang, Wei Lu, Liping Wang, Yapeng Fang, T Keith Blackwell, Ziyun Wu.
      Potassium is vital for life, yet how potassium homeostasis is maintained at the tissue or organismal level under dietary scarcity remains poorly understood. Stress-activated signaling pathway p38 MAPK is implicated in immune response and aging, but its specific role in low potassium response is unclear. Here we show that a specific p38 MAPK-ATF-7 pathway orchestrates cross-tissue potassium homeostasis in Caenorhabditis elegans. It drives transcriptional upregulation of a crucial P-type ATPase pump CATP-3 specifically in the hypodermis, a process that integrates cell-autonomous mechanisms with non-autonomous ASI neuronal signals, thereby enhancing organismal survival during potassium deficiency. Notably, this regulation is distinct from canonical osmotic stress responses, revealing a specialized and conserved survival strategy. Analogous p38-mediated control of P-type ATPases occurs in yeast and mammalian cells, suggesting broad relevance. Our findings redefine potassium regulation as a cross-tissue process linked to lifespan, stress signaling, and innate immunity with potential implications for aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-026-70641-7
  40. Nature. 2026 Mar 11.
    Intestinal interoceptive dysfunction drives age-associated cognitive decline.
    Timothy O Cox, Ashwarya S Devason, Alan de Araujo, Sydney Mason, Madhav Subramanian, Andrea F M Salvador, Hélène C Descamps, Junwon Kim, Yixuan Zhu, Lev Litichevskiy, Sunhee Jung, Won-Suk Song, Adrián Cortés-Martín, Nathan T Henderson, Kuei-Pin Huang, Thao Nguyen, Wisath Sae-Lee, Iboro C Umana, Maria Sacta, Ryan J Rahman, Stephen Wisser, J Andrew D Nelson, Ilona Golynker, Alana M McSween, Eric F Hohmann, Shaan Patel, Anna L Bub, Clara Soekler, Niklas Blank, Kevt'her Hoxha, Lavinia Boccia, Andrea C Wong, Klaas Bahnsen, Jihee Kim, Natalie Biderman, Dina Abbasian, Clarissa Shoffler, Christopher Petucci, Fiona E McAllister, Amber L Alhadeff, Marc V Fuccillo, Colin Hill, Cholsoon Jang, J Nicholas Betley, Guillaume de Lartigue, Virginia Y-M Lee, Maayan Levy, Christoph A Thaiss.
      Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population1. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome ageing and its functional consequences throughout the lifespan of mice, we identify a mechanism by which inhibition of gut-brain signalling during ageing results in impaired neuronal activation in the hippocampus and loss of memory encoding. Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signalling. As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened and hippocampal function declines. We leverage this pathway to define interventions that enhance memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition and restoration of vagal activity. These findings indicate a key role for interoceptive dysfunction in brain ageing and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.
    DOI:  https://doi.org/10.1038/s41586-026-10191-6
  41. Cell. 2026 Mar 10. pii: S0092-8674(26)00172-8. [Epub ahead of print]
    Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility.
    Jérémie Rispal, Jasmine R Garcia, Brisa Palikuqi, Manasa Vegesna, Dedeepya Vaka, Seung Woo Kang, Coralie Trentesaux, Juan Du, Nicola R Realini, Paige N Spencer, James M Gardner, Annika Hausmann, Michael G Kattah, Ken S Lau, Dario Boffelli, Ophir D Klein.
      The regionalized structure of the intestinal epithelium is critical for its function, and the risk for certain diseases has a regional bias. However, how regionalization is established and how it influences disease susceptibility remain poorly understood. Here, we investigated the role of the gut microbiome-the regionalized community of microorganisms in the intestinal lumen-in promoting regionalization of the colon. We found that the proximo-distal identity of colonocytes along the organ's length is disrupted in mice lacking a microbiome and that the proximal colonic microbiome produces high levels of nicotinic acid, which induces Pparα expression to establish proximal colonocyte identity. Furthermore, we report that microbiome-driven proximal identity confers protection against tissue injury in the mouse. Finally, we determined that the human colon is regionalized and loses its proximal identity during certain disease states.
    Keywords:  colon; colonocytes; dextran sodium sulfate; epithelium; host-microbiome interactions; inflammatory bowel disease; metabolism; microbiome; nicotinic acid; regionalization
    DOI:  https://doi.org/10.1016/j.cell.2026.02.007
  42. Nat Commun. 2026 Mar 09.
    Dual phagocytosis-checkpoint blockade revitalizes immune surveillance in mouse models of glioblastoma.
    JongHoon Ha, Yifan Wang, Yifan Ma, Annette Wu, Shiyan Dong, Seong Dong Jeong, Jared L Edwards, Mengyu Chang, Yen-Tzu Chang, Xiaotian Wang, Maurice Dufilho, Michelle Najarro Torres, Shannon McCabe, Weiye Deng, Adam J Grippin, Jeffrey S Weinberg, Shaan M Raza, Franco DeMonte, Ian E McCutcheon, Sujit Prabhu, Sherise D Ferguson, Chibawanye I Ene, Kadir Akdemir, Sreyashi Basu, Sonali Jindal, Benjamin R Schrank, Jian Hu, Sangeeta Goswami, Vinay K Puduvalli, Frederick F Lang, Kristin Huntoon, Padmanee Sharma, Betty Y S Kim, Wen Jiang.
      Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our results indicate that dual-phagocytosis checkpoint blockade offers a promising therapeutic avenue to potentiate cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-70221-9
  43. Nat Ecol Evol. 2026 Mar;10(3): 392-394
    How somatic evolution affects health.
    Alex Cagan.
      
    DOI:  https://doi.org/10.1038/s41559-026-03004-6
  44. 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
  45. Nature. 2026 Mar 10.
    'Virtual cell' captures the most-basic process of life: bacterial division.
    Ewen Callaway.
      
    Keywords:  Cell biology; Computational biology and bioinformatics
    DOI:  https://doi.org/10.1038/d41586-026-00786-4
  46. Genome Biol. 2026 Mar 11.
    Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control.
    Denzel Eggermont, Lissa Eggermont, Nagihan Aslantaş, Fabien Thery, Katie Boucher, Antje Beling, Bart Ghesquière, Francis Impens.
       BACKGROUND: Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) is implicated in the regulation of central carbon metabolism, but conflicting findings across experimental systems limit mechanistic insight. Here, we apply a multi-omics approach in cells ectopically expressing the ISGylation machinery independent of immune stimuli, to generate a systematic view of ISGylation in metabolic control.
    RESULTS: ISGylation preferentially targets metabolic enzymes, with marked enrichment among glycolytic proteins, suppressing the energy-yielding phase of glycolysis. Tracer metabolomics reveals a bottleneck at glyceraldehyde-3-phosphate dehydrogenase (GAPDH), reflected by accumulation of upstream intermediates and depletion of downstream metabolites. This arises from multisite ISGylation of lysines near its catalytic and regulatory regions, which reduces enzymatic activity without disrupting tetramer assembly.
    CONCLUSIONS: These findings identify GAPDH as a central metabolic checkpoint regulated by ISGylation and uncover a direct post-translational mechanism by which ISG15 controls energy metabolism.
    Keywords:  GAPDH; Glycolysis; ISG15; Mass spectrometry; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1186/s13059-026-04034-w
  47. Nat Commun. 2026 Mar 09.
    Heterogeneity in lysosomal dynamics and metabolic functions along the kidney proximal tubule.
    Monika Kaminska, Imene B Sakhi, Nevena Jankovic, Marcello Polesel, Andrew M Hall.
      The kidney proximal tubule is a highly specialized epithelium that transports metabolites and maintains body homeostasis. Cells lining this nephron segment are densely packed with lysosomes, but little is known about the dynamic activity of these organelles in situ. Here, using targeted sensors and live cell and intravital imaging we track acidified lysosomes along the mouse proximal tubule and uncover marked axial heterogeneity in their distribution, characteristics and organellar interactions. In the early part, cathepsin-rich lysosomes frequently contact with apical endosomes to receive and catabolize filtered plasma proteins. Conversely, in the later region, lipase-containing lysosomes traverse cells to mobilize and degrade mitochondria-associated lipid droplets and facilitate their extrusion into the tubular lumen. Acutely de-acidifying lysosomes dramatically alters their movement, causing major changes in tubular protein and lipid processing. Thus, lysosomes in proximal tubules are highly dynamic and adapted to perform distinct metabolic tasks within different specialized segments.
    DOI:  https://doi.org/10.1038/s41467-026-70306-5
  48. Nat Aging. 2026 Mar 13.
    Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.
    Pei-Lun Kuo, Ann Zenobia Moore, Toshiko Tanaka, Daniel W Belsky, Ake Tzu-Hui Lu, Steve Horvath, Stefania Bandinelli, Luigi Ferrucci.
      Epigenetic clocks derived from DNA methylation patterns are among the most promising biomarkers of biological aging1-7, as they capture molecular signatures that predict morbidity and mortality beyond chronological age. Although cross-sectional assessments of epigenetic age have been linked consistently to health outcomes and lifespan, it remains unclear whether the rate of change in these clocks over time provides additional insight into aging trajectories. In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.
    DOI:  https://doi.org/10.1038/s43587-026-01066-6
  49. Science. 2026 Mar 12. 391(6790): eaea9795
    Lifelong behavioral screen reveals an architecture of vertebrate aging.
    Claire N Bedbrook, Ravi D Nath, Libby Zhang, Scott W Linderman, Anne Brunet, Karl Deisseroth.
      Mapping behavior of individual vertebrate animals across lifespan could provide an unprecedented view into the lifelong process of aging. We created a platform for high-resolution continuous behavioral tracking of the African killifish across natural lifespan from adolescence to death. We found that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine-learning models accurately inferred age and even forecasted an individual's future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions, revealing precise structure for an architecture of aging.
    DOI:  https://doi.org/10.1126/science.aea9795
  50. Nat Cell Biol. 2026 Mar 13.
    Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer.
    Ming Liu, Anke Vandekeere, Xiao-Zheng Liu, Stephan Schenck, Juan Fernández-García, Tine Tricot, Yiming Peng-Winkler, Margherita Demicco, Dorien Broekaert, Ines Vermeire, Janine Theile, Gitte Zels, Anirudh Pabba, Christine Desmedt, Janine D Brunner, Patricia Altea-Manzano, Sarah-Maria Fendt.
      Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that KAT2A expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name ZDHHC20) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of KAT2A. Accordingly, Zdhhc20 and Tm4sf1 silencing as well as expression of a Tm4sf1 double palmitoylation mutant decreases lung metastasis growth, which is rescued by Kat2a expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.
    DOI:  https://doi.org/10.1038/s41556-026-01913-z
  51. J Clin Invest. 2026 Mar 10. pii: e196094. [Epub ahead of print]
    SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington's disease models.
    Mingqin Lu, Kexin Li, Shanshan Wu, Zhilong Zheng, Xinyue Li, Shengda Wang, Hanwen Yu, Chunyue Liu, Yueqing Jiang, Xueqin Song, Yan Liu, Xing Guo.
      Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and striatal neuron degeneration, primarily affecting medium spiny neurons (MSNs). Despite extensive research, the underlying metabolic vulnerabilities contributing to HD pathogenesis remain poorly understood. In this study, we employ RNA sequencing (RNA-seq) and metabolomics analyses to identify marked dysregulation of one-carbon metabolism in HD. We validate that SHMT2, a key mitochondrial enzyme in the mitochondrial one-carbon (mt-1C) pathway, is substantially downregulated in HD patient-derived iPSC-differentiated human striatal organoids (hSOs) and YAC128 mice. Functionally, pharmacological inhibition or genetic deletion of SHMT2 exacerbates mutant huntingtin (mHTT) aggregation, induces MSN degeneration in hSOs, and impairs motor function in WT mice. Conversely, SHMT2 overexpression attenuates MSN degeneration in HD-hSOs and improves motor performance in YAC128 mice. Mechanistically, SHMT2 deficiency leads to homocysteine (HCY) accumulation, which interacts with AARS1 and suppresses histone lactylation, thereby perturbing transcriptional regulation and associating with neurodegenerative phenotypes. Finally, we demonstrate that the HD clinical drug haloperidol modulates SHMT2 expression and restores histone lactylation, providing a pharmacological tool to probe SHMT2-dependent metabolic and epigenetic regulation in HD models. These findings highlight a metabolic-epigenetic axis as a promising therapeutic target for HD.
    Keywords:  Aging; Cell biology; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/JCI196094
  52. Trends Endocrinol Metab. 2026 Mar 10. pii: S1043-2760(26)00037-8. [Epub ahead of print]
    Communication breakdown: senescent cells in interorgan communication of aging.
    Rituparna Ghosh, Shweta S Dipali, Gabriela Desdín-Míco, Matthew J Yousefzadeh.
      Cellular senescence is a complex cell fate characterized by stable cell cycle arrest and other heterogeneous changes. Senescent cells play a causal role in aging, although the underlying mechanisms remain under active investigation. In this opinion article, we propose that senescent cells can act as key mediators of interorgan communication of aging. Recent work defines multifaceted mechanisms, including the production of senescence-associated secretory phenotype factors that act to propagate senescence signals to nearby and distant cells, as well as age-related alterations in immune function that drive chronic inflammation, known as 'inflammaging'. Further investigation of these mechanisms could yield improved strategies to target senescent cells and mitigate their effects on systemic aging via interorgan communication of aging.
    Keywords:  cellular senescence; immunosenescence; inflammaging; inflammation; interorgan aging
    DOI:  https://doi.org/10.1016/j.tem.2026.02.002
  53. Nat Aging. 2026 Mar 10.
    Simultaneous spatial transcriptomics and morphology profiling as tools to explore how microglia change with age.
    Douglas E Henze, Andy P Tsai, Tony Wyss-Coray, Stephen R Quake.
      Cellular morphology is tightly linked to function, but how subcellular transcript localization contributes remains unclear. Using microglia, the brain's resident macrophages, as a model, we combined multiplexed error-robust fluorescence in situ hybridization with immunohistochemistry to map how morphology and subcellular mRNA localization interact with function in young and aged mouse brains. We show that mRNA spatial organization varies across microglial states and defines distinct localization patterns within their processes, revealing morphological heterogeneity within transcriptomically defined populations. Notably, we found a subpopulation of disease-associated-like microglia with a ramified morphology (that is, displaying numerous processes), challenging the conventional assumption between morphology and microglial states. Finally, we found that aging may reshape mRNA distributions and their co-localization networks, shifting microglial programs from intracellular signaling and regulation of phagocytosis toward migration and catabolic regulation. Our findings highlight the role of subcellular transcript organization in shaping microglial morphology and function, offering new avenues for studying and modulating microglial states in health, disease and aging.
    DOI:  https://doi.org/10.1038/s43587-026-01089-z
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