bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–04–19
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Organellar insights in ageing and longevity.
  2. Tumour promotion through the lens of evolution.
  3. Overcoming dietary dogmas.
  4. Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
  5. Clonal biases dictate availability of colonic cancer driver mutations for transformation.
  6. Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity.
  7. A recipe for chaos: Extrachromosomal DNA and the hallmarks of cancer.
  8. SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
  9. Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits.
  10. Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
  11. mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.
  12. Glucose is dynamically regulated by time of day in humans and Drosophila.
  13. Fructose: metabolic signal and modern hazard.
  14. Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
  15. Organelle resilience as a comparative blueprint for longevity.
  16. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
  17. Cell death in cancer.
  18. p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
  19. Circadian clock gates diurnal glucose utilization.
  20. Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.
  21. Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
  22. Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
  23. Cancer ecosystems: A dynamic interplay across scales.
  24. Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
  25. Mapping intratumor heterogeneity across layers for advancing immunotherapy.
  26. Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code.
  27. Elevated levels of TNF and its targets characterize better-risk older acute myeloid leukemia patients.
  28. Scalable workflows for high-throughput respirometry.
  29. Purine salvage pathway protects CD8+ T cells from metabolic stress.
  30. Oxytocin signaling in adipocytes is required for normal milk fat production.
  31. The COX2-PGE2-PKA Axis Suppresses Antiviral Immunity by Inhibiting mtDNA-Dependent STING Activation.
  32. Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
  33. Circadian Timekeeping Through Nutritional and Metabolic Sensory Networks.
  34. Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
  35. Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
  36. Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.
  37. Metabolic secrets in a ubiquitous enzyme.
  38. Human Lymph Node Cellular Senescence Atlas Reveals Age-Dependent Alteration in Germinal Center B Cell Function and Niches.
  39. Cancer neuroscience: The past, the present, and the road ahead.
  40. Stress-induced proteome remodeling at the Golgi-endosome interface.
  41. An information content principle explains regulatory patterns of gene expression across human tissues.
  42. Early life exposure to N-nitrosamine drives genotoxicity, mutagenesis, and tumorigenesis in DNA repair-deficient mice.
  43. Beyond metabolic dormancy: metabolic rewiring in bacterial persistence.
  44. Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.
  45. Redox rhythms promote fitness by modulating ageing-dependent reprogramming.
  46. 5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
  47. Comparative analysis of naked mole-rat thermogenesis and its potential to maintain euthermia in response to cold.
  48. GPX1 dictates in vivo ferroptosis.
  49. Bridging the gap between organelles: Membrane contact sites as regulator of endocytic dynamics.
  50. Hallmarks of Cancer: How did it inspire you?
  51. The Hallmarks of Cancer: 25 years guiding discovery and therapy.
  1. Nat Cell Biol. 2026 Apr 17.
    Organellar insights in ageing and longevity.
    Philip Mannino, Mooncheol Park, Meng Carla Wang.
      Metabolic processes shape ageing and longevity at multiple levels. Emerging evidence shows that many of these processes are orchestrated within and between cellular organelles. Organelles function not only as metabolic reactors but also as signalling hubs, and their coordination plays crucial roles in maintaining cellular homeostasis and promoting organismal fitness. Rather than acting in isolation, organelles engage in dynamic crosstalk through membrane contact sites, metabolite exchange and signalling interplay. In recent years, organelles have been increasingly recognized as critical regulators of ageing and longevity. Here we summarize age-related organellar changes, highlight organelle-mediated intra- and intercellular signalling communication in lifespan and healthspan regulation, and discuss the active roles of organelles in microbiome-host interactions and transgenerational inheritance in regulating longevity. We further outline how longevity-promoting interventions influence organelles, and provide perspectives on how future technological advances may further accelerate progress in this emerging research topic.
    DOI:  https://doi.org/10.1038/s41556-026-01927-7
  2. Nature. 2026 04;652(8110): 591-601
    Tumour promotion through the lens of evolution.
    Nuria Lopez-Bigas, Eve Kandyba, Abel Gonzalez-Perez, Paul Brennan, Allan Balmain.
      Almost all tumours carry one or more cancer driver mutations, which are essential for cell transformation. However, recent advances in cancer genomics have demonstrated that normal human tissues contain millions of cells carrying known driver mutations, while preserving homeostasis. Most of these mutated cells will never transform into tumours. Moreover, studies of known or suspected human carcinogens have shown that the majority are not mutagens. These observations suggest that exogenous carcinogenic exposures might increase cancer risk by modifying selective constraints, promoting the expansion of pre-existing clones carrying specific oncogenic mutations. In this Review, we propose a synthesis between ideas put forward almost a century ago based on seminal experiments on carcinogen-induced tumours in mice, observations made by cancer epidemiologists over several decades, and the recent revelation that normal human tissues are a patchwork of mutant clones. The repeated interplay between variation and selection-the first principles of Darwinian evolution-underlies the clonal selection leading to tumorigenesis. A deeper understanding of these processes can enhance prospects for cancer prevention by eliminating or mitigating the effects of environmental or endogenous tumour promoters.
    DOI:  https://doi.org/10.1038/s41586-026-10386-x
  3. Nat Metab. 2026 Apr 15.
    Overcoming dietary dogmas.
    Jon O Lundberg, Martin O Bergo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01526-8
  4. Cell. 2026 Apr 15. pii: S0092-8674(26)00333-8. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Jin Park, Philipp Weiler, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masilionis, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
    Keywords:  KRAS inhibitors; benign-to-malignant transition; niche dynamics; p53; pancreatic cancer; single-cell biology; spatial transcriptomics; tumor initiation; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.03.032
  5. Nat Commun. 2026 Apr 16.
    Clonal biases dictate availability of colonic cancer driver mutations for transformation.
    Nefeli Skoufou-Papoutsaki, Richard Kemp, Sam Adler, Kate Marks, Anne-Claire Girard, Shenay Mehmed, Filipe C Lourenço, Elisa B Moutin, Rogier Ten Hoopen, Edward Morrissey, Douglas J Winton, David S Tourigny.
      Aged normal tissues harbour cancer mutations predisposing to transformation. However, how different pro-oncogenic events in the human colon compare in frequency, behaviour and subsequent transformation risk remains unclear. Here, we analyse mutation hotspot regions in five colorectal cancer genes (APC, KRAS, TP53, FBXW7 and CTNNB1) using targeted sequencing of 76,800 normal colonic glands from 56 patients. We show that cancer-driving mutations are present in all genes in histologically normal tissue. Reconstruction of clone dynamics reveals that FBXW7 R465C mutations preferentially become fixed within the tissue, whereas KRAS G12 mutations strongly promote expansion. Modelling mutation order indicates that early loss of both APC copies increasingly favours an APC-first pathway with age, while KRAS activation is equally likely to initiate events in younger individuals. Spatial transcriptomics highlights phenotypic heterogeneity among KRAS mutant clones, with mixed lineage presentation observed only in a subset, a state linked to elevated transformation risk in other organs.
    DOI:  https://doi.org/10.1038/s41467-026-71944-5
  6. Nature. 2026 Apr 14.
    Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity.
    Pantelis A Nicola, Andrew R J Lawson, Alexandra Tidd, Juliette Imbert, Yoshihiro Ishida, Luke A Wylie, Paul A Scott, Kenny Roberts, Luke M R Harvey, Stefanie V Lensing, Wei Cheng, Federico Abascal, Daniel Leongamornlert, Yvette Hooks, Matthew Mayho, Nicole Müller-Sienerth, Sara Widaa, Laura Mincarelli, James Illing, Flavia Peci, Bee Ling Ng, Georgeina L Jarman, Andrew J C Russell, Krishnaa T A Mahbubani, Kourosh Saeb-Parsy, Anna L Paterson, Krishna Chatterjee, Raheleh Rahbari, Omer Ali Bayraktar, Michael R Stratton, Peter J Campbell, John A Tadross, Nadia Schoenmakers, Iñigo Martincorena.
      Our immune system contains multiple checkpoints to prevent the activation of self-reactive lymphocytes. How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis posits that somatic mutations in immune-regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints1-3, but testing this has been challenging due to technical limitations. Here, we use whole-exome and targeted NanoSeq4,5, an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This revealed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes TNFRSF14 (HVEM) and CD274 (PD-L1), as well as less frequent mutations in other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones. Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing, and antibody synthesis localised these mutations to B cells, confirmed some to be self-reactive, and identified clones carrying multiple hits. We found widespread TNFRSF14 biallelic loss, and clones with as many as 4-6 driver mutations. Whilst each clone accounts for a small fraction of cells (typically <1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing new insights into the molecular basis of autoimmune disease.
    DOI:  https://doi.org/10.1038/s41586-026-10493-9
  7. Cell. 2026 Apr 16. pii: S0092-8674(26)00278-3. [Epub ahead of print]189(8): 2307-2321
    A recipe for chaos: Extrachromosomal DNA and the hallmarks of cancer.
    Ivy Tsz-Lo Wong, Chris Bailey, Sihan Wu, Anton G Henssen, Benjamin F Cravatt, Zhijian J Chen, Vineet Bafna, Mariam Jamal-Hanjani, Charlie Swanton, Howard Y Chang, Paul S Mischel.
      Some aggressive cancers exhibit a level of rapid genome change and therapy resistance that is difficult to explain. Research over the past decade has shown that extrachromosomal DNA (ecDNA) can be the cause. When oncogenic genetic elements untether from chromosomes and no longer follow Mendelian inheritance, genomic chaos and accelerated evolution ensue, generating unique ecDNA biology and non-traditional therapeutic vulnerabilities distinct from traditional mutation-targeting approaches. Here, we put forward a holistic view where ecDNA is integrated into the broader Hallmarks of Cancer framework to better understand the problem and chart a path forward.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.011
  8. bioRxiv. 2026 Apr 07. pii: 2026.04.03.716311. [Epub ahead of print]
    SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
    Dingcheng Sun, Guangrui Ding, Haonan Lin, Guo Chen, Chun-Chin Wang, Seema Bachoo, Sarah E Bohndiek, Ji-Xin Cheng.
      Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.
    DOI:  https://doi.org/10.64898/2026.04.03.716311
  9. Nat Commun. 2026 Apr 11.
    Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits.
    Clair Crewe, Christy M Gliniak, Toshiharu Onodera, Shiuhwei Chen, Jan-Bernd Funcke, May-Yun Wang, Snigdha Tiash, Yun-Ling Pai, Marjori Russo, Saket Awadhesbhai Patel, Ze Yu, Yi-Cian Zheng, Alex Larkin, Chao Xing, Laurent Gautron, Chun-Kan Chen, Chen Liu, Philipp E Scherer.
      Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.
    DOI:  https://doi.org/10.1038/s41467-026-71740-1
  10. Mol Cell Proteomics. 2026 Apr 15. pii: S1535-9476(26)00065-4. [Epub ahead of print] 101569
    Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
    Colin Zenge, Brittany Q Pham, Kihong Nam, Elana Apfelbaum, Heeseon An, Alban Ordureau.
      Altered metabolism is a hallmark of cancer, making metabolic enzymes attractive therapeutic targets. However, metabolic inhibitors have shown limited clinical success, partly due to differences between standard culture media and physiological nutrient conditions. Human plasma-like medium (HPLM) better recapitulates in vivo metabolite concentrations, yet its effects on cellular proteomes remain poorly characterized. We performed comprehensive TMTpro-based quantitative proteomics and phosphoproteomics across nine cancer cell lines cultured in DMEM or HPLM, consistently quantifying over 10,000 proteins and 24,000 phosphorylation sites across all three biological replicates with high reproducibility. Physiological media induced profound cell-type-specific remodeling of metabolic networks, mitochondrial proteomes, and signaling pathways. While decreased mTORC1 and CDK activity represented universal responses across all cell lines, metabolic enzyme expression exhibited striking heterogeneity. Enzymes in folate metabolism and pyrimidine salvage pathways showed consistent reductions across all cell types, indicating that drug responses may vary with media choice. Mitochondrial proteome composition and morphology displayed cell-type-specific adaptations. Phosphoproteomic analysis revealed kinase signaling networks underlying these metabolic changes. This dataset, accessible via an interactive web application, provides a resource for metabolic research using physiological media, highlighting substantial cell-type-specific variability in how media affect proteomes and signaling pathways.
    Keywords:  CDK activity; Cancer cell metabolism; Physiological Media; Proteomics; mTORC1 signaling
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101569
  11. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00195-4. [Epub ahead of print]86(8): 1546-1559.e8
    mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.
    Thomas A O'Loughlin, John S Stiles, Pritika Acharya, Abolfazl Arab, Laine Goudy, Raymond Dai, Ashir A Borah, William A Weiss, Uche N Medoh, Luke A Gilbert.
      Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common feature of cancer, but while mTOR kinase represents an attractive drug target, mTOR inhibitors have not seen broad success as single agents. To identify strategies to enhance the utility of third-generation bi-steric mTORC1 inhibitors, we performed genome-scale CRISPR interference chemogenomics screens, which revealed that mTORC1 inhibitor-mediated cytostasis leaves cells exquisitely dependent on the lipid peroxide scavenging enzyme GPX4. Mechanistically, using unbiased CRISPR activation chemogenomics screens, we demonstrate that mTORC1-dependent control of ferroptosis occurs, in part, through regulation of SCARB1 expression. Specifically, we find that the high-density lipoprotein (HDL) can suppress ferroptosis through interaction with its receptor SCARB1 and delivery of vitamin E to target cells. Our work highlights combining mTORC1 with GPX4 inhibition as one of the most promising combinatorial approaches for mTOR-targeted cancer therapies and defines an HDL-SCARB1 ferroptosis-suppression system that is regulated by mTORC1 activity.
    Keywords:  GPX4; HDL; SCARB1; antioxidant; cancer; cell biology; ferroptosis; functional genomics; lipoprotein; mTOR; tocopherol; vitamin E
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.019
  12. PLoS Biol. 2026 Apr;24(4): e3003717
    Glucose is dynamically regulated by time of day in humans and Drosophila.
    Dania M Malik, Pinky Kain, Seth D Rhoades, Arjun Sengupta, Shirley L Zhang, Annika Barber, Paula Haynes, Erna Sif Arnardottir, Allan Pack, Richard G Kibbey, Amita Sehgal, Aalim M Weljie.
      Biological clocks shape metabolism, but how circadian programs govern nutrient processing is unclear. Here, using human metabolomics and 13C6-glucose tracing in Drosophila, we delineate previously under characterized daily oscillations in glucose-derived metabolic networks, providing a mechanistic framework for a purpose-built isotope-tracing approach. In flies, we reveal a pronounced "rush hour" of glucose utilization early in the light phase, with carbons directed to biosynthetic and energetic pathways. By contrast, a dopamine reuptake-deficient hyperactive mutant (fumin) with elevated metabolic rate shows phase-shifted and amplified metabolic peaks, indicating that altered neural signaling reshapes temporal glucose flux. Neither altered feeding schedules nor short-term fasting disrupt these intrinsic metabolic rhythms, strongly suggesting that circadian timing, rather than nutrient availability, orchestrates temporal homeostasis. By integrating human metabolite profiling with isotope-tracing in flies, we define a conserved temporal architecture of glucose utilization and demonstrate that metabolic flux is dynamically gated across the day. Our findings establish a framework for understanding how circadian misalignment contributes to metabolic dysfunction and disease.
    DOI:  https://doi.org/10.1371/journal.pbio.3003717
  13. Nat Metab. 2026 Apr 17.
    Fructose: metabolic signal and modern hazard.
    Richard J Johnson, Miguel A Lanaspa, Dean R Tolan, Marcus D Goncalves, Samir Softic, Kimber L Stanhope, Laura G Sánchez-Lozada, Mark A Herman, Joshua D Rabinowitz.
      There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose's well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular and physiological distinctions between fructose and glucose, as well as the endogenous fructose pathway that makes fructose from glucose. Through this Review, we highlight the role of fructose not only as a caloric source, but also as a regulator of metabolic health and disease.
    DOI:  https://doi.org/10.1038/s42255-026-01506-y
  14. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12
    Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
    Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.
      Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.
    Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
  15. EMBO Mol Med. 2026 Apr 16.
    Organelle resilience as a comparative blueprint for longevity.
    Domagoj Cikes.
      The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longevity remain largely genome-centric, although genomic instability alone cannot comprehensively explain aging-related pathologies. Many age-associated failures emerge at the level of cellular organelles whose stability underpins tissue function. The pathways that sustain these structures operate through proteomic, metabolic, and lipid networks that are insufficiently captured by genomic or transcriptomic analyses. Notably, longer organismal lifespan increases the requirement for sustained organelle functionality and fidelity. This Perspective proposes that the next conceptual advance in geroscience will come from comparative organelle biology. Examining mammals with divergent lifespans, including species evolutionarily closer to humans, can reveal how long-lived lineages evolved organelle-level architecture and resilience mechanisms that support cellular function over decades. I introduce the Comparative Metabolic Longevity Cell Atlas (CMLCA), a cross-mammalian platform integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis to identify conserved features of resilience and inform next-generation strategies to improve human healthspan.
    DOI:  https://doi.org/10.1038/s44321-026-00428-2
  16. Nat Aging. 2026 Apr 13.
    Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
    Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.
      Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging. Thus, complement C3a reduction is a metabolically regulated inflammatory checkpoint that can be harnessed to attenuate inflammaging.
    DOI:  https://doi.org/10.1038/s43587-026-01107-0
  17. Cell. 2026 Apr 16. pii: S0092-8674(26)00325-9. [Epub ahead of print]189(8): 2322-2356
    Cell death in cancer.
    Marcus Conrad, Andreas Strasser, Philipp J Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida.
      "Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.024
  18. Nat Aging. 2026 Apr 16.
    p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
    Ivan A Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A Soto, Alexander J Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D J Lopez Gonzalez, Matthew R Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M Koehler, Jesse G Meyer, Julia J Mack, Charles Brenner, Steven J Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J Lusis, Anthony J Covarrubias.
      Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01101-6
  19. PLoS Biol. 2026 Apr;24(4): e3003743
    Circadian clock gates diurnal glucose utilization.
    Yao D Cai, Joanna C Chiu.
      The circadian clock and cellular metabolism are tightly coupled to maintain homeostasis. A new study in PLOS Biology leverages metabolic tracing to reveal time-of-day-dependent activities of glucose metabolic pathways in Drosophila that are disrupted in clock and sleep mutants.
    DOI:  https://doi.org/10.1371/journal.pbio.3003743
  20. Nat Immunol. 2026 Apr 14.
    Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.
    Qi-Xiang Ma, Ru Zhao, Jiang-Xue Han, Wen-Ying Zhu, Mi-Die Xu, Xiao-Yan Zhang, Guo-Quan Yan, Wen-Yu Wen, Guang-Chun Han, Min Luo, Miao Yin, Jin-Tao Li, Qun-Ying Lei.
      Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context. Here, using clinical samples and genetically engineered mouse tumor models, we showed that tumor-derived BCKAs are secreted actively into the tumor microenvironment (TME) where they reprogram tumor-associated macrophages (TAMs) to promote tumor progression. Through genome-wide CRISPR screening, we identified Notch2 as a direct molecular target of BCKAs. BCKAs activate Notch signaling by binding to and stabilizing cleaved Notch2, functionally reprogramming TAMs and fostering an immunosuppressive TME. Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.
    DOI:  https://doi.org/10.1038/s41590-026-02484-9
  21. Cell Metab. 2026 Apr 15. pii: S1550-4131(26)00106-3. [Epub ahead of print]
    Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
    Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.
      Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
    Keywords:  DNA methylation; dendritic cells; electron transport chain; immunity; metabolites; mitochondria; redox balance
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.012
  22. Nat Rev Immunol. 2026 Apr 15.
    Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
    Neil T Sprenkle, Evanna L Mills.
      Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s41577-026-01292-4
  23. Cell. 2026 Apr 16. pii: S0092-8674(26)00270-9. [Epub ahead of print]189(8): 2441-2463
    Cancer ecosystems: A dynamic interplay across scales.
    Daniela F Quail, Johanna A Joyce.
      Tumors evolve within complex, adaptive ecosystems that operate across spatial, temporal, and systemic scales. Within each tumor microenvironment, numerous diverse cell populations assemble into specialized niches that are continually shaped by systemic physiology, environmental inputs, and therapeutic pressure. Beyond the local microenvironment, cancer progression is governed by the host macroenvironment, where intrinsic biological determinants intersect with modifiable factors to collectively impact physiological fitness and tissue resilience. Here, we propose a multi-scale framework that unites tumor biology with organismal physiology and reframes therapy from eliminating malignant cells in isolation to reprogramming the cellular, vascular, and systemic networks that sustain disease. We highlight emerging approaches that aim to restore physiological equilibrium, spanning from spatial multi-omics and AI-driven pathology to immune-vascular normalization and physiological conditioning. Together, these dimensions define an integrative vision for precision oncology that bridges discovery and intervention to achieve durable and ultimately curative cancer therapy.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.003
  24. Cells. 2026 Apr 02. pii: 646. [Epub ahead of print]15(7):
    Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
    Ursula Rauch-Kroehnert, Jacqueline Heger, Ulf Landmesser, Andrea Dörner.
      Adenine nucleotide translocase (ANT) has traditionally been defined as the ADP/ATP exchanger of the inner mitochondrial membrane. However, accumulating mechanistic evidence reveals a substantially broader functional spectrum that extends beyond nucleotide transport. In this review, we integrate these advances into a unified conceptual framework that positions ANT isoforms as modulators of mitochondrial bioenergetics, quality control, and cellular communication. Beyond its canonical exchange activity, ANT influences permeability transition thresholds and membrane potential stability, participates in regulated uncoupling and redox control, and contributes to inner membrane organization and cristae integrity. ANT further modulates TIMM23-dependent protein import and PINK1-Parkin-mediated mitophagy, thereby shaping mitochondrial quality control decisions. In addition, ANT regulates mitochondrial nucleic acid release and inflammasome activation, linking bioenergetic imbalance to innate immune signaling. Emerging evidence for alternative subcellular localizations suggests that ANT-dependent signaling extends mitochondrial state information to extracellular and intercellular contexts. Collectively, these findings support an expanded view of ANT as a multifunctional modulator linking mitochondrial energetic state to stress adaptation, inflammatory signaling, and tissue-level communication.
    Keywords:  adenine nucleotide translocase; dsRNA transport; extracellular vesicles; immunometabolism; mitochondrial dynamics; mitochondrial permeability transition pore; mitochondrial signaling; mitochondrial uncoupling; mitophagy; mtDNA stability
    DOI:  https://doi.org/10.3390/cells15070646
  25. Cell. 2026 Apr 16. pii: S0092-8674(26)00326-0. [Epub ahead of print]189(8): 2416-2440
    Mapping intratumor heterogeneity across layers for advancing immunotherapy.
    Jean-Christophe Marine, Osnat Bartok, Shira Sagie, Pietro Paolo Vitiello, Alberto Bardelli, Chen Weller, Tian-Gen Chang, Claudia Tonelli, Stefani Spranger, Eytan Ruppin, Yardena Samuels.
      Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and plasticity generate dynamic cancer cell states with distinct immune visibility. These layers of complexity converge on the immunopeptidome, the repertoire of peptides displayed by major histocompatibility complex molecules through which tumor cells are surveyed by T cells. Variation in antigen processing, presentation, and peptide abundance across cancer clones and cell states yields spatially and temporally distinct immunological niches that shape immune recognition and therapeutic response. Here, we summarize how multidimensional ITH manifests across cancer types and constrains immunotherapy efficacy. We propose that integrating measurements across layers is a promising direction for improving biomarker identification and informing more precise immune-based treatment strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.025
  26. Genome Res. 2026 Apr 15. pii: gr.281022.125. [Epub ahead of print]
    Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code.
    Marina Murillo, Marina Salvadores, Aina Vaquer Picó, Lina Tsapanou, Adrian Gabriel Torres, Fran Supek, Lluis Ribas de Pouplana.
      Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the T2T version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNA species capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration.
    DOI:  https://doi.org/10.1101/gr.281022.125
  27. Leukemia. 2026 Apr 13.
    Elevated levels of TNF and its targets characterize better-risk older acute myeloid leukemia patients.
    Yaseswini Neelamraju, Franck Rapaport, Jorge A Gandara, B Bishal Paudel, Susan DeWolf, Nicholas Dunham, Hao Fan, Tak Lee, Marty W Mayo, Jad Othman, Caroline Sheridan, Katia Sol-Church, Michael Dimitri Solga, Ling Wang, Larry D Cripe, Richard Dillon, Maria Kleppe, Martin Carroll, Christopher E Mason, Gail J Roboz, Zhuoxin Sun, Martin S Tallman, Yanming Zhang, Elisabeth Paietta, Ross Levine, Ari M Melnick, Stefan Bekiranov, Francine E Garrett-Bakelman.
      
    DOI:  https://doi.org/10.1038/s41375-026-02954-x
  28. Life Sci Alliance. 2026 Jun;pii: e202503446. [Epub ahead of print]9(6):
    Scalable workflows for high-throughput respirometry.
    Corey A Osto, Eugene V Mosharov, Ayelet M Rosenberg, Martin Picard, Linsey Stiles, Orian Shirihai.
      Mitochondrial respirometry, the measurement of oxygen consumption rate (OCR) by the electron transport chain (ETC), is a cornerstone of mitochondrial biology and the gold standard for measurements of mitochondrial function. However, existing respirometry methodologies are poorly suited for large-scale studies and high-throughput applications, ultimately limiting the applicability of these methods. This limitation necessitates new methodologies, which are more easily scaled as mitochondrial studies become more complex and diverse. In this study, we detail a respirometry approach we have developed for high-throughput applications including optimized plate layouts, volume-based sample normalization, robust control selection, and automated data processing and quality control. Furthermore, we validate these methodologies across a respirometry study running 703 human brain samples, totaling more than 10,000 data points, which underwent our automated data processing and quality control techniques. Our workflow streamlines assay preparation, execution, and analysis to make respirometry scalable, while reducing operator burden and preserving data integrity. With this study, we provide a transferable blueprint for high-throughput respirometry as the mitochondrial biology field and the studies within it continue to expand in scale.
    DOI:  https://doi.org/10.26508/lsa.202503446
  29. Nat Immunol. 2026 Apr 13.
    Purine salvage pathway protects CD8+ T cells from metabolic stress.
    Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-Ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan.
      Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.
    DOI:  https://doi.org/10.1038/s41590-026-02491-w
  30. Cell Metab. 2026 Apr 16. pii: S1550-4131(26)00107-5. [Epub ahead of print]
    Oxytocin signaling in adipocytes is required for normal milk fat production.
    Erwei Li, Yangmian Yuan, Haijing Sun, Khushi Patel, Nan Zhang, Soumya Nagesh, Juan J Aristizabal-Henao, Michael Kiebish, Christopher Jacobs, Dave Bridges, Brigid Gregg, Evan D Rosen.
      Milk triglycerides, a crucial nutrient source for newborn mammals, can be derived from adipose lipolysis, dietary sources, or de novo synthesis in mammary epithelial cells (MECs). Here, we identify a critical role for the neuropeptide oxytocin (OXT) in providing milk triglyceride needed to sustain neonatal growth, mediated by its actions on adipose lipolysis. Dams lacking OXT receptors (OXTRs) specifically in adipocytes (OxtrΔAd) give birth to pups with reduced weight gain. Oxytocinergic sympathetic neurons are the relevant source of OXT mediating this effect. Milk from OxtrΔAd dams was deficient in triglycerides, which could be rescued by liberalizing dietary fat intake. Finally, single-cell analysis of lactating mammary glands from OxtrΔAd dams revealed a profound shift in the metabolic programming of MECs, indicative of reduced mTOR signaling, increased autophagy, and reduced lipid synthesis. These findings highlight the critical role of OXT-mediated adipose lipolysis in mammalian lactation, demonstrating that lipolysis-derived free fatty acids (FFAs) are essential for normal milk fat and neonatal health.
    Keywords:  growth restriction; lactation; lipolysis; mammary gland; milk lipid; oxytocin
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.013
  31. bioRxiv. 2026 Apr 06. pii: 2026.04.03.716411. [Epub ahead of print]
    The COX2-PGE2-PKA Axis Suppresses Antiviral Immunity by Inhibiting mtDNA-Dependent STING Activation.
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind.
      The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA) to induce type I interferon (IFN) response, which is essential for mounting the antiviral response. However, STING activation during viral infection is often insufficient to achieve complete viral clearance, suggesting the existence of additional mechanisms that evade its activity. Here, we identified COX2/PGE 2 as a negative regulator of STING activation, particularly in response to arising cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, PGE 2 , through the EP4-cAMP-PKA axis, induces mitophagy to remove defective mitochondria and hence prevent the accumulation of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated type I IFN and antiviral response. Furthermore, we identified STOML2 as a downstream target of PKA that connects mitochondrial quality control with the regulation of innate immune signaling. Together, our findings establish the COX2/PGE 2 /PKA axis as a negative regulator of mtDNA-STING signaling that may be targeted to potentiate STING-mediated type I IFN and innate immunity.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2026.04.03.716411
  32. EMBO Rep. 2026 Apr 14.
    Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
    Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma.
      Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes.　In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.
    Keywords:  Glycerol; Inflammation; Macrophage; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/s44319-026-00747-y
  33. Nutrients. 2026 Mar 31. pii: 1133. [Epub ahead of print]18(7):
    Circadian Timekeeping Through Nutritional and Metabolic Sensory Networks.
    Erin N Doherty, Lauren N Woodie.
      Circadian rhythms are predictable biological patterns that recur about every 24 h and, in mammals such as humans, are entrained to daylight by the hypothalamic suprachiasmatic nucleus (SCN). Although light is a potent zeitgeber for the SCN, cells outside of the SCN can synchronize to daily nutrient and metabolic cues. In these tissues, nutrient metabolic processes are regulated by the molecular clock in anticipation of food availability or scarcity. Furthermore, nutrients and metabolic processes themselves may act upon members of the molecular clock to regulate their expression and activity. These interactions maintain synchrony between the SCN and food-entrainable clocks when activity and nutrient intake align. However, the light-entrainable SCN and food-entrainable clocks can become desynchronized, particularly in modern society where humans are commonly exposed to shift work and jet lag. Therefore, the mechanisms for sensing nutrients at specific times of day are critical components of circadian timekeeping and organismal homeostasis. In the following narrative review, we aim to synthesize current evidence on time-of-day-dependent nutrient sensing in mammalian systems, examine how nutrient-derived signals and metabolic processes interact with molecular clock mechanisms across cellular and tissue levels, and evaluate the integration of central and peripheral clocks in regulating gene expression, energy utilization, and organismal homeostasis, including the impacts of feeding cycles and circadian disruption. While previous reviews have discussed circadian nutrient metabolism, this review provides conceptual support for the role of nutrients as time-of-day signaling mechanisms.
    Keywords:  circadian rhythms; metabolism; nutrition; sensory
    DOI:  https://doi.org/10.3390/nu18071133
  34. Nat Commun. 2026 Apr 14.
    Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
    Yingfan Zhang, Hailey A Parry, Laura Reyes, Alex Shamoun, Junhui Sun, Chengyu Liu, Danielle Springer, Audrey Noguchi, Sachiko Nakamori, Angel M Aponte, Jeeva Munasinghe, Raul Covian, Elizabeth Murphy, Brian Glancy.
      Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na+/Ca2+ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca2+. Consistently, TMEM65 ablation caused loss of Na+-dependent mitochondrial Ca2+ export. Notably, blocking mitochondrial Ca2+ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca2+ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca2+ overload.
    DOI:  https://doi.org/10.1038/s41467-026-71761-w
  35. Nature. 2026 Apr 15.
    Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
    Julian R Buissant des Amorie, Joris H Hageman, Sascha R Brunner, Suzanne E M van der Horst, Maria C Puschhof, Arne van Hoeck, Inge van Lierop, Sjors Middelkamp, Lisa van der Schee, Sven van Kempen, Folkert Morsink, Robin Geene, Sander Mertens, David S Cavigelli, Ingrid Verlaan-Klink, Lianne J Kraaier, Jorieke Salij, Renate Bezemer, Onno Kranenburg, Miangela M Laclé, Leon M G Moons, Hugo J G Snippert.
      Metastasis formation is classically considered a late-stage event in colorectal cancer evolution. Yet the time and spatial patterning by which metastatic competence is acquired remain poorly understood1,2. Here we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of colorectal cancer, concurrent with invasive front formation. However, although necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting extra bottlenecks such as immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumour progression stages within individual early-stage colorectal cancers. Whole-genome sequencing and growth factor-dependency assays exclude tumour cell-intrinsic acquired traits. By contrast, single-cell spatial atlases of the tumour microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid cocultures confirm that these trophocyte-like cancer-associated fibroblasts induce plastic transitioning to oncofetal states. Thus, interactions between tumour and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during colorectal cancer progression.
    DOI:  https://doi.org/10.1038/s41586-026-10344-7
  36. Nat Commun. 2026 Apr 15.
    Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.
    Verena Wagner, Laura Bousset, Mariana Ascensão-Ferreira, Bin Sun, José Efren Barragan Avila, Alexandre Kaizeler, Rita Martins-Silva, Mohammad Rahbari, Mirian Fernández-Vaquero, Scott Haston, Michele Tinti, Joaquim Pombo, Sanjay Khadayate, Susanne Roth, Christian M Schürch, Juan Pedro Martínez-Barbera, Anat Bahat, Keng Boon Wee, Jennifer P Morton, Nisar Malek, Andrew J Innes, Santiago Vernia, Nuno L Barbosa-Morais, Suchira Gallage, Mathias Heikenwalder, Jesús Gil.
      RAS family proteins, including HRAS, NRAS, and KRAS, are frequently mutated in cancer. Although there has been recent success in designing inhibitors that target oncogenic RAS, they elicit resistance and treating RAS-driven cancer remains difficult. Here, employing a proteomic analysis, we find that multiple spliceosome components are upregulated in the nuclei of cells undergoing RAS-induced senescence. This upregulation depends on RAS signalling and occurs in both senescent preneoplastic and fully transformed cancer cells. Spliceosome components are also highly expressed in preneoplastic and cancerous lesions in human and murine lung, liver, colorectal, and pancreatic cancers. Using siRNA screens, we identify six spliceosome components, including SF3B1 and RBM39, that are essential in cells expressing oncogenic RAS. We find that SF3B1 is required in these cells for maintaining splicing fidelity. By combining transcriptome and splicing analyses with functional screens, we identify the RNA Pol II-associated factor SPT5 as a key mediator of the SF3B1 effects. Importantly, using mouse models of liver cancer, we show that RBM39 and SF3B1 inhibitors are effective in targeting both preneoplastic lesions and aggressive tumours expressing oncogenic RAS. In summary, our study highlights the spliceosome as a promising target for RAS-driven cancers capable of inhibiting both cancer initiation and progression.
    DOI:  https://doi.org/10.1038/s41467-026-71564-z
  37. Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00102-7. [Epub ahead of print]
    Metabolic secrets in a ubiquitous enzyme.
    Dan Kehila, Paola Laurino.
      Recent work by Sakuma et al. shows that the ubiquitous enzyme alkaline phosphatase (PhoA) can oxidize phosphite, revealing a new metabolic role for a classic catalytic generalist. Despite its relatively low efficiency, PhoA's global distribution and conservation indicate that it may substantially influence phosphite turnover and highlight the significance of enzymatic multifunctionality.
    Keywords:  alkaline phosphatase (PhoA); catalytic generalist; enzyme promiscuity; metabolic evolution; phosphite oxidation; phosphorus metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.002
  38. bioRxiv. 2026 Apr 06. pii: 2026.04.02.716161. [Epub ahead of print]
    Human Lymph Node Cellular Senescence Atlas Reveals Age-Dependent Alteration in Germinal Center B Cell Function and Niches.
    Negin Farzad, Archibald Enninful, Yao Lu, Fabio Parisi, Anthony Fung, Yumi Kwon, Yajuan Li, Margaux Labrosse, Mingyu Yang, Francesco Strino, Liang Chen, Junchen Yang, Mei Zhong, Fu Gao, Bo Tao, Joseph Cunningham, Zhiliang Bai, Haikuo Li, Fang Wang, Michael Stankewich, Dongjoo Kim, Mingze Dong, Lisa M Bramer, Keyi Li, Meera R Bhat, Evan Loe, Joseph Craft, Ljiljana Pasa-Tolic, Stephanie Halene, Lingyan Shi, Yuval Kluger, Mina L Xu, Rong Fan.
      Immunosenescence, the age-associated decline in immune function, is a key feature of human aging. In human lymphoid organs, however, the specific immune cell populations that acquire senescence-associated phenotypes during aging and how they influence the surrounding tissue microenvironment remain poorly understood. A spatially resolved map of these senescence-associated immune states in human lymphoid tissues could help clarify their relationship with aging and their potential contributions to the progressive decline of immune function. Here, we integrated single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs). Single-cell transcriptomics of lymphoid tissues from donors aged 18 to 100 years old identified 34 immune and stromal cell types and revealed age-associated upregulation of senescence signatures in specific populations. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence (∼20 million cells) mapped senescence markers (p16, p21, HMGB1, 𝛾 -H2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal center (GC) localization with age. Notably, we observed focal clonal-like senescence in GC B cells in older donor LNs. Spatial transcriptomics, epigenomics, and metabolic imaging of selected samples further elucidate the multi-omics signatures and underlying mechanisms of functional impairment, metabolic remodeling, and distinct regulatory programs in senescent-like GC B cells. This study presents a comprehensive spatial atlas of senescence-associated immune states in human lymph nodes, revealing cell-type-specific and spatial heterogeneity that may contribute to immunosenescence and the decline of immune function during aging.
    DOI:  https://doi.org/10.64898/2026.04.02.716161
  39. Cell. 2026 Apr 16. pii: S0092-8674(26)00285-0. [Epub ahead of print]189(8): 2464-2489
    Cancer neuroscience: The past, the present, and the road ahead.
    Frank Winkler, Sophie Heuer, Ferdinand Althammer, Hellmut Augustin, Filippo Beleggia, Ihsan Ekin Demir, Julian Koenig, Rohini Kuner, Thomas Kuner, Sonja Loges, Michael Platten, Hans Christian Reinhardt, Judith M Rich, Felix Sahm, Ruth Martha Stassart, Vera Thiel, Andreas Trumpp, Varun Venkataramani, Wolfgang Wick, Matthia A Karreman.
      Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.018
  40. J Cell Sci. 2026 Apr 16. pii: jcs.264535. [Epub ahead of print]
    Stress-induced proteome remodeling at the Golgi-endosome interface.
    Gina Simon, Savina Abraham Pol, Melisa Dendusic, Nina Schulze, Simone Stupia, Michelle Koci, Lana Buzuk, Beatrice Thier, Philine Steinbach, Hai Trinh, Jasmin Schillinger, Sabrina Ninck, Farnusch Kaschani, Markus Kaiser, Michael Ehrmann, Annette Paschen, Doris Hellerschmied.
      Cellular stress response pathways support cell survival under stress and are often leveraged by cancer cells to gain advantageous traits. How cells respond to Golgi apparatus (Golgi) stress is incompletely understood, limiting insights into the role of Golgi stress in cancer. Here, we combined small molecule stress models and proteomic analyses to elucidate stress-induced changes at the Golgi. Our data establish the depletion of Golgi transport proteins as a common response to different Golgi stressors, including ionophores and inhibitors of the Oxysterol binding protein (OSBP). Ionophores further induce de novo expression of the stress response protein FAM129A/NIBAN1, which localizes to the remodeled secretory pathway. In a group of melanoma cells, displaying a dedifferentiated epithelial-to-mesenchymal-transition (EMT)-like phenotype, FAM129A is constitutively expressed. In these cells, stress-induced localization of FAM129A to the secretory pathway is achieved by relocalization from the plasma membrane. Collectively, our data highlight the Golgi-endosome interface as a critical hub of the cellular response to Golgi stress and reveal cancer cell specific effects of this response.
    Keywords:  Chemical biology; FAM129A/NIBAN1; Golgi stress; Ionophores; Melanoma
    DOI:  https://doi.org/10.1242/jcs.264535
  41. Nat Commun. 2026 Apr 11.
    An information content principle explains regulatory patterns of gene expression across human tissues.
    Ruthie Golomb, Maayan Yoles, Simon Fishilevich, Bar Cohen, Sapir Savariego Peled, Dvir Dahary, David Gokhman, Yitzhak Pilpel.
      Gene expression ranges from broadly expressed to tissue-specific patterns, with many genes displaying intermediate specificity. Understanding how regulatory architecture scales with tissue specificity can reveal fundamental principles of genome regulation. By analyzing cis-regulatory element counts across human genes with varying tissue specificity, we identify a non-monotonic pattern: genes with intermediate specificity harbor the most regulatory elements, suggesting distinct regulatory strategies across the expression spectrum. We apply the Minimum Description Length principle from information theory, and maximum parsimony from phylogenetics, to quantify regulatory demand underlying expression patterns. This measure scales consistently with cis-regulatory element counts, transcription factors, microRNAs, and gene structure, and distinguishes switch-like regulation in selectively expressed genes from fine-tuning regulation in broadly expressed genes. Regulatory element abundance peaks in genes of intermediate evolutionary age. Regulatory architecture appears to scale with informational costs, suggesting that the genome operates as a decompression device, where regulation is dictated by minimally required complexity.
    DOI:  https://doi.org/10.1038/s41467-026-71279-1
  42. Nat Commun. 2026 Apr 14.
    Early life exposure to N-nitrosamine drives genotoxicity, mutagenesis, and tumorigenesis in DNA repair-deficient mice.
    Lindsay B Volk, Monét Norales, Callie Karjane, Joshua J Corrigan, Alper J Alcaraz, Lee J Pribyl, Nicolette A Bugher, Megan Blawas, Isabella Dulski, Einthavy Arunachalam, Nina Gubina, Emily Michelsen, Kannammai Pichappan, Natalya Yakimchuk, Matilda Swanson, Duanduan Ma, Stuart S Levine, Desiree L Plata, Robert G Croy, Leona D Samson, John M Essigmann, Carole L Yauk, Sebastian E Carrasco, Bevin P Engelward.
      N-Nitrosodimethylamine (NDMA) is a probable human carcinogen found in contaminated pharmaceuticals and drinking water, yet the impact of age on NDMA susceptibility remains poorly understood. Using DNA repair-deficient (Aag-/-;Mgmt-/-) and wild-type mice, we systematically compare the effects of NDMA exposure in juveniles and adults. Juvenile Aag-/-;Mgmt-/- mice are profoundly more vulnerable, exhibiting persistent DNA damage, inflammation, and mutations that lead to liver pathology and tumorigenesis, particularly in males. Adults, by comparison, are resistant to NDMA. Wild-type mice show similar, attenuated trends. NDMA-induced DNA adduct levels are comparable across age groups, implicating proliferation-dependent responses to adducts, rather than adduct formation, as the primary driver of age-related risk. Supporting this mechanism, triiodothyronine-stimulated cell proliferation in adults partially recapitulates juvenile sensitivity, linking cell division to NDMA genotoxicity. Our findings identify developmental stage, sex, and DNA repair capacity as key modifiers of NDMA-induced carcinogenesis, with potential implications for environmental risk assessment and regulatory policy.
    DOI:  https://doi.org/10.1038/s41467-026-71753-w
  43. Nat Commun. 2026 Apr 16. pii: 3536. [Epub ahead of print]17(1):
    Beyond metabolic dormancy: metabolic rewiring in bacterial persistence.
    Mehmet A Orman, Han G Ngo, Sayed Golam Mohiuddin.
      Bacterial persister cells that exhibit a transient state of antibiotic tolerance play a key role in chronic and recurring infections. Despite advances in our understanding of persisters, many aspects of their phenotypic plasticity, particularly their metabolism, are poorly characterized. In this Perspective, we examine the static and dynamic characteristics of persister metabolism that are shaped by genetics, environmental cues, and the intrinsic variability in cellular processes. These factors underlie much of the diversity observed among persister cells and largely explain the inconsistency in expression of classic persister hallmarks such as biphasic killing curves or metabolic dormancy. Further, the literature suggests that persisters are not uniformly metabolically dormant but represent a range of metabolic states. We will focus on the unique rewiring of the metabolic mechanisms in persisters, which depends on both internal and external factors.
    DOI:  https://doi.org/10.1038/s41467-026-71427-7
  44. Cell Chem Biol. 2026 Apr 13. pii: S2451-9456(26)00074-7. [Epub ahead of print]
    Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.
    Alex E Ekvik, Megan M Kober, Denis V Titov.
      The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to alterations in the energy state by sensing changes in the ratio of ATP, ADP, AMP, and inorganic phosphate levels. A key barrier to understanding how this happens is a lack of tools for direct manipulation of the energy state in living cells. Here, we introduce ATPGobble-a genetically encoded tool that hydrolyzes ATP in vivo. ATPGobble increases the metabolic rate, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK in human cells. We performed a systematic analysis of proteome and phosphoproteome changes caused by ATPGobble, and found that it remodels cytoskeleton, cell cycle, and translation machinery. Our results establish ATPGobble as a powerful new tool for dissecting the regulatory roles of energy state in living cells.
    Keywords:  AMPK; ATP; ATP/ADP ratio; F1 ATPase; cell fitness; energy status; energy stress; genetically encoded tools; phosphoproteomics; proteomics
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.004
  45. Nat Metab. 2026 Apr 17.
    Redox rhythms promote fitness by modulating ageing-dependent reprogramming.
    Xiaoman Wang, Shen-Shen Cui, Xun-Kai Li, Si-Yao Qu, Wei-Wei Chang, Ao Tang, Yu Jin, Shi-Juan Peng, He-Ping Wang, Xue-Qin Fang, Li-Yuan Lu, Chen-Xi Lv, Xin Yu, Jing-Yao Peng, Si-Si Wang, Zi-Yu Wei, Yu-Tong Zhu, Hui-Yu Wang, Jia-Qi Fu, Wen-Qi Li, Ying-Ying Jin, Hou-Zao Chen, Jian-Fei Pei, De-Pei Liu.
      Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.
    DOI:  https://doi.org/10.1038/s42255-026-01515-x
  46. EMBO Rep. 2026 Apr 13.
    5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
    Jimmy Ly, Eric M Smith, Matteo Di Bernardo, Yi Fei Tao, Elizabeth M Black, Ekaterina Khalizeva, Iain M Cheeseman.
      The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5' UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5' UTR length, including a deletion in the VHL 5' UTR in von Hippel-Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5' UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome.
    DOI:  https://doi.org/10.1038/s44319-026-00776-7
  47. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2600755123
    Comparative analysis of naked mole-rat thermogenesis and its potential to maintain euthermia in response to cold.
    Aleksei Mikhalchenko, June K Corrigan, Yuchen He, Zalan Peterfi, Sun Hee Yim, Sang-Goo Lee, Zhaoming Deng, Vince G Amoroso, Vera Gorbunova, Andrei Seluanov, Thomas J Park, Alexander S Banks, Vadim N Gladyshev.
      The naked mole-rat (NMR) is a subterranean rodent known for its unique thermal biology, exceptional longevity, and resistance to cancer and hypoxia. However, its thermal biology remains controversial, with various reports describing NMRs as poikilotherms, heterotherms, mesotherms, or partial homeotherms. Here, we investigated whether the thermogenic potential of NMR brown adipose tissue and its UCP1 differ from those in mice and whether the lack of thermal insulation causes extreme changes in NMR body temperature upon cold exposure. Through longitudinal molecular, thermal, metabolic, and behavioral measurements, we found that NMRs initiated nonshivering thermogenesis and elevated body temperature but could not sustain it due to excessive heat loss. Our results suggest that NMRs represent a unique thermoregulatory category that does not fit neatly into traditional classifications. In vitro and in vivo experiments showed that the NMR UCP1 is functional and can be activated and inhibited as expected for most other mammals. We further demonstrated that artificial insulation can partially restore thermoregulatory capabilities in NMRs. This study employs an advanced methodology to characterize the thermal biology of NMRs and helps resolve a long-standing controversy in the field.
    Keywords:  aging; longevity; metabolism; naked mole-rat; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2600755123
  48. Nat Cell Biol. 2026 Apr;28(4): 650
    GPX1 dictates in vivo ferroptosis.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-026-01935-7
  49. Curr Opin Cell Biol. 2026 Apr 11. pii: S0955-0674(26)00029-3. [Epub ahead of print]100 102641
    Bridging the gap between organelles: Membrane contact sites as regulator of endocytic dynamics.
    Giorgia Miloro, Margherita Caputo, Pier Paolo Di Fiore, Sara Sigismund.
      Endocytosis controls the internalization of molecules, receptors and membrane components, thereby regulating nutrient uptake, signaling and membrane composition. Increasing evidence shows that trafficking of endocytic cargo is coordinated by membrane contact sites (MCSs). Rather than passive bridges, MCSs act as dynamic platforms that organize communication between organelles, integrating metabolic and biochemical signals with spatial precision. Their ability to locally remodel membranes and generate spatially confined signaling domains directly shapes endocytic and endo-lysosomal trafficking. MCSs are also highly adaptive: they remodel in response to extracellular cues such as growth factors and can be exploited by pathogens to create replication-permissive niches, positioning MCSs as central hubs of intracellular organization and communication.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102641
  50. Cell. 2026 Apr 16. pii: S0092-8674(26)00324-7. [Epub ahead of print]189(8): 2203-2205
    Hallmarks of Cancer: How did it inspire you?
    Lucas T Jae, Lillian L Siu, Lei Zhang, Anwesha Dey, Lisa M Coussens, Gerard Evan.
      In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the framework continues to guide discovery, encourage collaboration across disciplines, and inspire new ways to better understand and treat cancer.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.023
  51. Cell. 2026 Apr 16. pii: S0092-8674(26)00334-X. [Epub ahead of print]189(8): 2195-2196
    The Hallmarks of Cancer: 25 years guiding discovery and therapy.
    Cell Editorial Team
      Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding of cancer, guided drug development, and evolved to incorporate new discoveries and address emerging challenges.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.033
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