bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–06–14
sixty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondria tethered to the nucleus secure its energy supply.
  2. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  3. Mitochondria-ER contacts function as an iron supply hub.
  4. Placental nicotinamide adenine dinucleotide modulates the timing of labor.
  5. Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
  6. Attack of the clones: Tracing the dynamics of innate immune cells in human cancer.
  7. Mitochondrial transfer reveals an organellar layer of cancer ecology.
  8. Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
  9. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
  10. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  11. Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.
  12. DNA repair drives cisplatin-induced neuronal death.
  13. Cell size modulates ferroptosis susceptibility.
  14. Why machine learning fails at mass spectrometry for small molecules.
  15. SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.
  16. Cell size-dependent mRNA transcription drives proteome remodeling.
  17. Hormetic fasting extends Caenorhabditis elegans lifespan via H3K27 acetylation of lipid catabolism and antioxidant genes.
  18. MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
  19. Somatic mutations in autoimmunity.
  20. Inflammatory cytokines induce new cancer dependencies.
  21. Reduced Myocardial Serine Synthesis Impairs Functional, Metabolic, and Redox Adaptations to Cardiac Stress.
  22. Hyperglycosylation is a metabolic driver of Alzheimer's disease.
  23. A gustatory receptor-Akt axis couples nutrient sensing to hematopoiesis in the silkworm.
  24. Gut microbiota and metabolic control of immune checkpoint blockade in cancer.
  25. Human Genome-Scale Models of Metabolism and Gene Expression Reveal Resource Constraints of Cancer Cell Lines.
  26. Model-based inference of enzyme inhibitions from perturbation-induced metabolic dynamics.
  27. SenCat: Cataloging human cell senescence through multi-omic profiling of multiple senescent primary cell types.
  28. Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
  29. Hp1bp3 loss links chromatin reorganization to metabolic vulnerability in glioma.
  30. Gregory J. Hannon (1964-2026).
  31. Mitochondria directly interact with the nuclear pore complex.
  32. SPACE-seq integrates spatial transcriptomics and lineage tracing in native tissues.
  33. Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.
  34. Mitochondrial permeability transition in redox homeostasis and ferroptosis.
  35. LARP1 integrates MYC and mTOR signaling to enable anabolic growth during tumor initiation.
  36. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  37. Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
  38. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  39. The placental metabolic clock.
  40. Rise in sugar decoration in Alzheimer's disease.
  41. The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2.
  42. Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling.
  43. Charting human cellular senescence in aging and disease.
  44. Vacuole pH loss triggers ESCRT-dependent plasma membrane remodeling to prevent amino acid toxicity.
  45. Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
  46. Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages.
  47. STING dampens the unfolded protein response to enable the presentation of self-antigens on MHC-I during inflammation.
  48. Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets.
  49. Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
  50. Significance of GSH and H2S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health.
  51. L-type voltage-gated Ca2+ channels control T cell killing via non-canonical Hedgehog signalling.
  52. Intrinsic and extrinsic regulators of cancer dormancy and awakening.
  53. Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
  54. Cell stress and death liberate the autophagy-inhibitory tissue stress hormone DBI/ACBP into the circulation.
  55. Mutation-dependent responses to sleep and exercise in clonal haematopoiesis.
  56. Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
  57. Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding.
  58. Single-cell whole-genome sequencing reveals convergent evolution in Burkitt lymphoma.
  59. Guardian of two galaxies: Senescence-associated immune cells control disease tolerance and aging.
  60. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  61. A DNA damage-activated kinase phosphorylates a transcriptional repressor to control bacterial immune pathway expression.
  62. Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
  63. In situ reprogramming of CAR-alveolar macrophages via liposomal nanomedicine for lung cancer immunotherapy.
  64. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  65. Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer.
  1. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  2. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  3. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  4. Science. 2026 Jun 11. 392(6803): 1194-1199
    Placental nicotinamide adenine dinucleotide modulates the timing of labor.
    Erin J Ciampa, Luana M Machado, Kathy J Lee, Amanda J Clark, Kyle Q Vu, Nawal A Khan, Sarah Kispert, Samantha Armstrong, Yunping Li, Ginger L Milne, Ashley Solmonson, S Ananth Karumanchi, Samir M Parikh.
      Labor is mediated proximately by prostaglandin signaling within gestational tissues and must be tightly regulated for birth to occur after appropriate fetal development. Metabolic changes accompanying gestational aging have been postulated as a determinant of birth timing, but specific nutrients, sensors, and messengers remain obscure. We report that placental nicotinamide adenine dinucleotide (NAD+) dynamically tunes gestational length. Depletion of placental NAD+ in mice provoked labor onset, mediated by the role of NAD+ as a cofactor for 15-hydroxy prostaglandin dehydrogenase, an enzyme responsible for suppressing prostaglandin accumulation. Augmentation of placental NAD+ prolonged gestation at baseline and in a model of preterm labor. These findings suggest a central role for metabolic exhaustion in provoking labor and reveal potential therapeutic avenues for preterm labor and the optimization of labor induction.
    DOI:  https://doi.org/10.1126/science.adz1624
  5. J Cell Biol. 2026 Aug 03. pii: e202507174. [Epub ahead of print]225(8):
    Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
    Marjana Ndoci, Sharanya Bhattacharya, Ishita Agrawal, Yvonne Hinze, Kathrin Lemke, Anna-Lena Schumacher, Esther Uijttewaal, Ulrich Elling, Steffen Lawo, Patrick Giavalisco, Thomas Langer, Soni Deshwal.
      Coenzyme Q (CoQ) is a hydrophobic lipid primarily synthesized in the mitochondria, though it is also present in non-mitochondrial membranes. However, the metabolic pathways that regulate intracellular CoQ distribution are unknown. This study identifies a key role for the mevalonate pathway in regulating CoQ distribution. The mevalonate pathway synthesizes isopentenyl pyrophosphate (IPP) as the precursor metabolite for both CoQ and cholesterol. We show that CoQ synthesis remains stable regardless of whether the mevalonate pathway is upregulated or downregulated. Upregulation of HMG-CoA reductase (HMGCR), indicative of increased mevalonate flux, enhances cholesterol ester synthesis without altering CoQ levels. When the pathway is downregulated, cholesterol synthesis declines, yet mitochondrial CoQ levels are preserved. Under these limiting conditions, mitochondria reduce CoQ export to maintain their internal CoQ pool. While this adaptation sustains mitochondrial respiration, it diminishes extramitochondrial CoQ availability and sensitizes cells to ferroptosis. These findings uncover a mitochondria-driven mechanism that preserves respiratory function by prioritizing CoQ retention during metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202507174
  6. Cancer Cell. 2026 Jun 11. pii: S1535-6108(26)00258-8. [Epub ahead of print]
    Attack of the clones: Tracing the dynamics of innate immune cells in human cancer.
    Amir Brivanlou, Nir Hacohen.
      In this issue of Cancer Cell, Liu et al. use mitochondrial DNA mutations to reconstruct clonal lineages of the innate immune compartment in human tumors. They show that intratumoral type 3 dendritic cells (DC3s) arise from circulating monocytes and that a monocyte's fate in the tumor microenvironment is programmed peripherally, prior to tissue entry.
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.013
  7. Trends Cancer. 2026 Jun 11. pii: S2405-8033(26)00113-5. [Epub ahead of print]
    Mitochondrial transfer reveals an organellar layer of cancer ecology.
    Derick Okwan-Duodu, Bo Li, Edgar Engleman.
      Tumors are ecological systems shaped by continuous exchange with surrounding cells. The transfer of functional mitochondria, which reprograms malignant behavior, introduces a distinct layer to this ecology. Cancer evolution may proceed not solely through mutation and selection but also through the horizontal assimilation of organellar traits acquired from neighboring cells.
    Keywords:  cancer hallmarks; metabolism; metastasis; mitochondrial transfer; organellar ecology
    DOI:  https://doi.org/10.1016/j.trecan.2026.05.006
  8. Cell. 2026 Jun 11. pii: S0092-8674(26)00570-2. [Epub ahead of print]189(12): 3506-3508
    Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
    Melanie Grusdat, Dirk Brenner.
      T cells live or die by their metabolism, yet one nutrient can serve very different ends. In this issue of Cell, Kelly et al. show that cysteine's sulfur is partitioned between glutathione and iron-sulfur cluster synthesis. This routing drives CD8+ T cell proliferation, effector function, and anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.011
  9. bioRxiv. 2026 Jun 03. pii: 2026.05.30.724257. [Epub ahead of print]
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Hannah J Richter, Sabina Chubanava, Yann Deleye, Zafir Kaiser, Yachen Shen, Ditte Neess, Frederike Sass, Fabian Finger, Lidia Argemi Muntadas, David Tandio, Tao Ma, Elahu Gosney Sustarsic, Hannes Embring, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucinska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew Paul Gillum, Terry D Hinds, Raymond Edward Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Susanne Mandrup, Brice Emanuelli, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERBα. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPARα. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.
    DOI:  https://doi.org/10.64898/2026.05.30.724257
  10. Neuron. 2026 Jun 09. pii: S0896-6273(26)00386-7. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Yingzhi Ye, Minghua Fan, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a potential therapeutic target for AD.
    Keywords:  Alzheimer’s disease; CMPK2; KAT7; cGAS-STING; microglia; mitochondrial DNA; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2026.05.015
  11. Cancer Res. 2026 Jun 06.
    Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.
    Dazhi Wang, Timothy M Horton, Kyutae David Lee, Ifeanyichukwu Chinedu Ogobuiro, Fatemeh Vatankhah, Isadora de Andrade, John C Pisano, Vijay S Thakur, Mia K Gurevich, Sam Taylor, Mohammad Alyamani, Durga Prasad Gannamedi, Daniel G Isom, David B Lombard, Anthony J Griswold, Nima Sharifi, Vanina T Tcheuyap, James Brugarolas, Mark L Gonzalgo, Oleksandr N Kryvenko, Scott M Welford.
      Despite the presence of oxygen, tumors frequently preferentially perform fermentative glycolysis, producing lactate and acidifying the tumor microenvironment. Although studies have observed that high concentrations of lactate in the tumor microenvironment help tumors gain a proliferative advantage, a detailed understanding of the molecular mechanisms is needed to uncover strategies to overcome lactate-mediated growth. Here, we investigated how lactate exerts pro-growth effects in clear cell renal cell carcinoma (ccRCC), a highly glycolytic tumor primarily caused by alterations in the von Hippel-Lindau tumor suppressor and constitutive activation of HIF signaling. High lactate concentrations activated GPR132, a lactate sensor highly expressed by ccRCC, which conferred pro-tumor growth signaling by elevating mitochondrial respiration through the ERK/STAT3/JAK2 pathway. Furthermore, GPR132 facilitated the uptake of lactate through elevation of HIF signaling downstream of AKT/mTOR to fuel mitochondrial respiration in a feed-forward manner. Treatment with a small molecule GPR132 antagonist demonstrated the essentiality of GPR132 to support ccRCC growth in vivo. Together, these findings reveal that GPR132 signaling promotes ccRCC by sustaining mitochondrial integrity and elevating lactate import. The crosstalk between lactate and tumor cells is a metabolic vulnerability that can be disrupted by targeting GPR132, providing a potential treatment strategy for ccRCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3236
  12. Cell. 2026 Jun 10. pii: S0092-8674(26)00584-2. [Epub ahead of print]
    DNA repair drives cisplatin-induced neuronal death.
    William J Nathan, Chuanyuan Chen, Rosy Sakr, Bruno Siqueira Mietto, Vincent van Batenburg, Jeroen van den Berg, Josette J Wlaschin, Ferenc Livak, Elsa Callen, Nancy Wong, Eliza Y H Lloyd, Hanna Silberberg, Sushma Sharma, Raj Chari, Tzipporah Freeman, Baek Kim, Alexander van Oudenaarden, Alexander T Chesler, Michael E Ward, Lisa D Boxer, Peter J McHugh, Andrei Chabes, Claire E Le Pichon, André Nussenzweig.
      Platinum agents are cornerstone therapies for many cancers but often cause neurotoxicity in post-mitotic tissues, for which effective interventions are lacking. This limitation reflects an incomplete understanding of neuronal responses to DNA damage. We show that nucleotide excision repair (NER) mediates cisplatin lesion removal in neurons; however, unlike its protective role in dividing cells, NER promotes neuronal death in response to cisplatin. This vulnerability arises because neurons possess low deoxynucleoside triphosphate (dNTP) pools. dNTPs are initially consumed during transcription-coupled NER to resolve transcription-blocking lesions. As dNTP levels become depleted, repair fails to complete, leading to accumulation of double-strand breaks, particularly during global-genome NER. Supplementation with deoxynucleosides or genetic upregulation of dNTP synthesis restores nucleotide pools, protects neurons from cell death, and reduces cisplatin-induced neuropathic pain. These findings identify limited dNTP availability as a key vulnerability in post-mitotic cells and suggest nucleoside supplementation as a potential strategy to mitigate chemotherapy-induced neurotoxicity.
    Keywords:  DNA repair; chemotherapy; cisplatin; deoxynucleotides; neuron; neuropathy; neurotoxicity; nucleotide excision repair
    DOI:  https://doi.org/10.1016/j.cell.2026.05.025
  13. Elife. 2026 Jun 10. pii: RP111544. [Epub ahead of print]15
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    Keywords:  biochemistry; cell biology; cell death; cell size; chemical biology; erastin2; ferroptosis; glutathione; heterogeneous response; human; scaling
    DOI:  https://doi.org/10.7554/eLife.111544
  14. Nat Metab. 2026 Jun 11.
    Why machine learning fails at mass spectrometry for small molecules.
    Ling Min Serena Khoo, Regina Barzilay.
      
    DOI:  https://doi.org/10.1038/s42255-026-01544-6
  15. Sci Adv. 2026 Jun 12. 12(24): eaec8873
    SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.
    Anna Marsal-Beltran, Laura Salmerón-Pelado, Aleix Ribas-Latre, Maria Repollés-de-Dalmau, M-Mar Rodríguez-Peña, Catalina Núñez-Roa, Joan Badia, Ana Madeira, Eva Novoa, Marc Beltrà, Ana Belén Plata-Gómez, Jordi Capellades, Joan Carles Escolà-Gil, Antonio Zorzano, Óscar Yanes, Alejo Efeyan, Ruben Nogueiras, Jordi Gracia-Sancho, Joan Vendrell, Victòria Ceperuelo-Mallafré, Sonia Fernández-Veledo.
      Succinate, a mitochondrial metabolite, also functions as an extracellular signal through its receptor succinate receptor 1 (SUCNR1), coordinating responses to nutrient availability. The physiological role of SUCNR1 within hepatocytes, however, is unclear. We show that hepatic succinate levels and Sucnr1 expression are dynamically regulated by nutritional status. Mice lacking Sucnr1 in hepatocytes [Hep-Sucnr1 knockout (KO)] exhibit a fasting-like phenotype characterized by enhanced gluconeogenesis, elevated amino acids, and impaired metabolic flexibility. Mechanistically, loss of Sucnr1 compromises glucose-derived oxidative flux through the tricarboxylic acid cycle, increases reliance on glutamine-dependent anaplerosis, and induces mitochondrial stress adaptations. Upon refeeding, Hep-Sucnr1 KO mice show blunted mammalian target of rapamycin activation, incomplete glycogen restoration, and an altered hepatic proteomic response. Sucnr1 expression increases during liver maturation, is enriched in pericentral hepatocytes, and its loss is associated with functional reprogramming of pericentral metabolic functions without disruption of zonation. Together, our findings establish SUCNR1 as a critical regulator of hepatic metabolic adaptation, linking succinate signaling to mitochondrial flexibility and nutrient-dependent metabolic responses.
    DOI:  https://doi.org/10.1126/sciadv.aec8873
  16. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00566-8. [Epub ahead of print]45(6): 117488
    Cell size-dependent mRNA transcription drives proteome remodeling.
    Dong Shin You, Christopher H Bohrer, Purva H Rumde, Ioannis Sanidas, Matthew P Swaffer, Daniel R Larson, Josh E Elias, Michael C Lanz, Jan M Skotheim.
      Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.
    Keywords:  CP: molecular biology; bursting; cell biology; cell size; homeostasis; lysosome; scaling; single-molecule imaging; transcription; turnover
    DOI:  https://doi.org/10.1016/j.celrep.2026.117488
  17. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00596-6. [Epub ahead of print]45(6): 117518
    Hormetic fasting extends Caenorhabditis elegans lifespan via H3K27 acetylation of lipid catabolism and antioxidant genes.
    Yifei Zhou, Fasih M Ahsan, Sainan Li, Mengjiao Song, Jen F Rotti, Armen Yerevanian, Yidong Shen, Alexander A Soukas.
      Exposure to low levels of environmental challenges, known as hormetic stress, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. Here, we identify histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. Induced H3K27ac at metabolic genes, mediated by the pioneer factor PHA-4/FOXA, the cooperating transcription factor NHR-49/HNF4, and the nucleoporin 50 (NPP-16/NUP50), is crucial for lifespan extension under hormetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch bridging nutrient status with transcriptomic reprogramming, underpinning the longevity of hormetic fasting through orchestrating lipid catabolism and antioxidant defenses.
    Keywords:  CP: Metabolism; CP: Molecular biology; aging; antioxidant defense; epigenetic modification; fasting; histone acetylation; longevity; metabolic rewiring; nuclear pore complex; nutrient stress
    DOI:  https://doi.org/10.1016/j.celrep.2026.117518
  18. Autophagy. 2026 Jun 13.
    MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
    Ming-Hua Wu, Xue-Ming Zhu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.
      Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in Magnaporthe oryzae remains poorly understood. In our recent study, we found that upon outer mitochondrial membrane disruption, inner mitochondrial membrane (IMM) protein MoCox6 is rendered available for engagement with cytosolic MoAtg5 and MoAtg14 to drive mitophagy, whereas MoSirt5-mediated desuccinylation of MoCox6 at K144 weakens these interactions and thereby restrains mitophagic flux. Further analyses identified Asp95 at the MoSirt5-MoCox6 interface as a pivotal residue coupling mitochondrial metabolic control to mitophagy. A high-throughput virtual screening targeting an Asp95-centered pocket in MoCox6 identified Pan-RAS-IN-1, a small molecule that effectively suppresses rice blast incidence and exhibits broad-spectrum antifungal activity. Collectively, these findings identify MoCox6 as an IMM regulator of mitophagy whose succinylation state links mitochondrial metabolic cues to mitochondrial turnover, while highlighting mitochondrial quality control as a potential target for fungal disease management.
    Keywords:  Fungicide target; MoCox6; magnaporthe oryzae; mitophagy; succinylation
    DOI:  https://doi.org/10.1080/15548627.2026.2689458
  19. Nat Genet. 2026 Jun;58(6): 1200
    Somatic mutations in autoimmunity.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-026-02653-4
  20. Nat Genet. 2026 Jun;58(6): 1353-1367
    Inflammatory cytokines induce new cancer dependencies.
    Collins K Cheruiyot, Sarah Y Kim, Juan Dubrot, Sarah K Lane-Reticker, Alex Miranda, Ashwin V Kammula, Jonathan J Perera, Peter P Du, Cun Lan Chuong, Rachel A Fetterman, Nelson H Knudsen, Aiping Jiang, Juliette S M T Suermondt, Lomax F Pass, Cong Fu, Meng-Ju Wu, Lei Shi, Seth Anderson, Audrey J Muscato, Omar I Avila, Ian C Kohnle, Emily A Kessler, Hans W Pope, Sarah G Noel, Kira E Olander, Jooho Chung, Kayla J Colvin, Nabeel Bardeesy, Kathleen B Yates, Robert T Manguso.
      Tumor cells respond and adapt to environmental stresses that facilitate growth in hostile environments, including cytokine-mediated inflammation elicited by antitumor immunity and enhanced by immune checkpoint blockade (ICB). However, cytokine responses also induce transcriptional and cell-state changes that may predispose tumor cells to new vulnerabilities, which remain poorly explored. Here we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to interferon-γ (IFNγ), interferon-β or tumor necrosis factor to map inflammation-induced genetic vulnerabilities. We identified members of the glycosylphosphatidylinositol (GPI) transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 markedly enhanced response to ICB in vivo. By integrating functional genomics, metabolomics and pharmacologic perturbation of downstream stress pathways, we found that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in paraptosis-like cell death. Collectively, these findings identify tumor-intrinsic dependencies governing responses to inflammatory cytokines.
    DOI:  https://doi.org/10.1038/s41588-026-02614-x
  21. bioRxiv. 2026 Jun 02. pii: 2026.05.29.728910. [Epub ahead of print]
    Reduced Myocardial Serine Synthesis Impairs Functional, Metabolic, and Redox Adaptations to Cardiac Stress.
    Malihe Rezaee, Mohammad Keykhaei, Navid Koleini, Tegbir Panesar, Simiao Li, Nalini Salvekar, David J Polhemus, Chengchen Hu, Mariam Meddeb, Liang Zhao, Kavita Sharma, Christopher Petucci, Nathaniel Snyder, Junichi Sadoshima, David A Kass.
       Background: Impaired myocardial metabolism is a defining feature of heart failure, but many defective pathways and mechanisms remain to be identified. Prior studies find phosphoglycerate kinase and its synthesized product 3-phospho-glycerate required for the serine synthetic pathway (SSP) are reduced in human HFpEF myocardium. As serine is also provided exogenously, the impact of SSP reduction is uncertain. Here, we tested if and how SSP decline coupled to phosphoglycerate dehydrogenase (PHGDH) impacts cardiomyocyte (CM) and whole heart metabolic remodeling and stress responses.
    Methods: Studies were performed in isolated CMs and mice with CM-selective knock-down of PHGDH. Using pharmacological inhibition or genetic silencing of PHGDH, we tested their impact on CM one-carbon metabolism pathways, cell hypertrophic responses, mitochondrial respiration, and in vivo functional, structural, and metabolic adaptations to pressure-overload stress.
    Results: In CMs, PHGDH inhibition caused dose-dependent serine depletion linearly coupled with cytotoxicity, accompanied by NAD/NADH and GSH/GSSG imbalance, reduced ATP, and disruption of one-carbon and nucleotide metabolites. Stable-isotope tracing revealed distinct metabolic fates of glucose-derived (SSP) versus exogenous serine. Exogenous serine did not rescue PHGDH-deficient CMs, whereas combined ribose and an anti-oxidant (DTT) attenuated injury and reduced nucleotide pools. PHGDH suppression reduced amino acid abundance, impaired nascent protein synthesis, and blunted endothelin-1-induced hypertrophic and mitochondrial respiration. In vivo , cardiomyocyte-specific PHGDH heterozygous mice (PHGDH +/- ) had no basal phenotype, but amplified chamber dilation, dysfunction, fibrosis, and mortality 4 weeks after transverse aortic constriction (TAC). Corresponding increases in amino acids, one-carbon metabolites, nucleotides, and TCA-cycle intermediates in wild-type TAC hearts were significantly blunted in PHGDH +/- hearts.
    Conclusions: Cardiomyocyte SSP is a critical regulator of redox balance, one-carbon metabolism, purine synthesis, amino acid homeostasis, and growth-related pathways required for cardiac adaptation to pressure overload. It is non-redundant with exogenous serine by providing distinct influences on key metabolic pathways and is a potential therapeutic target.
    DOI:  https://doi.org/10.64898/2026.05.29.728910
  22. Nat Metab. 2026 Jun 09.
    Hyperglycosylation is a metabolic driver of Alzheimer's disease.
    Tara R Hawkinson, Zizhen Liu, Roberto A Ribas, Terrymar Medina, Rikke S Nielsen, Harrison A Clarke, Xin Ma, Angela C Mueller, Adrielle F Plasencia, Alexander L Sheer, Samantha T Simpson, Charles M Soto, Jessica Sudderth, Feng Cai, Alex R Cantrell, Matthieu G Colpaert, Cameron J Shedlock, Lei Wu, Lyndsay E A Young, Damon D Kooser, Li Chen, Alison M Ryan, Sadi Quinones, Jihye Son, Parastoo Azadi, Ralph J Deberardinis, Stefan Prokop, Derek Allison, Shuang Yang, Hongyu Chen, Yu Huang, Xing He, Kimberly M Alonge, Jingchuan Guo, Yi Guo, Jiang Bian, Craig W Vander Kooi, Matthew S Gentry, Ramon C Sun.
      Alzheimer's disease (AD) is a devastating neurodegenerative disorder marked by progressive cognitive decline. Metabolic disruptions are widely observed, yet their involvement in the molecular aetiology of AD remains underexplored. Here we identify hyperglycosylation as a driver of AD. Integrating spatial metabolomics, lipidomics and glycomics in transgenic AD mouse models and post-mortem human AD samples, along with advanced spatial isotopic tracing pulse-chase analysis of N-linked glycans, we demonstrate that the conserved phenotype of brain hyperglycosylation is driven by increased glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes improves cognitive outcomes in AD mice whereas oral glucosamine supplementation impairs them. A retrospective analysis of electronic health records from patients with AD with varying disease severity shows that glucosamine supplementation is associated with accelerated AD progression and worsened survival. Overall, these results establish hyperglycosylation as a pathological driver of AD and highlight glycan metabolism as an actionable target in the fight against AD.
    DOI:  https://doi.org/10.1038/s42255-026-01538-4
  23. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2535199123
    A gustatory receptor-Akt axis couples nutrient sensing to hematopoiesis in the silkworm.
    Wenjing Zhang, Shogo Uno, Ryoichi Sato, Dingze Mang.
      Hematopoiesis is tightly linked to an organism's metabolic state, yet the molecular sensors that convert nutrient availability into hematopoietic output remain poorly understood. Here, we identify a fructose-sensitive gustatory receptor, BmGr9, as a cell-intrinsic nutrient sensor that links circulating sugar levels to blood cell proliferation in the silkworm Bombyx mori. We show that fructose, whose concentration rises sharply after feeding, stimulates hematopoietic organ (HPO) proliferation through BmGr9-dependent Ca2+ influx and activation of the Akt-ornithine decarboxylase/polyamine signaling pathway. CRISPR/Cas9-mediated knockout of BmGr9 reduces hemocyte production and impairs fructose-induced Akt phosphorylation and polyamine synthesis. We further demonstrate that the fat body polyol pathway produces fructose de novo, which then acts as an interorgan metabolic signal that promotes hematopoiesis and shapes gene expression in the wing-disc/hematopoietic complex. Together, these findings define a nutrient-receptor-signaling axis that mechanistically links dietary and endogenous fructose to hematopoietic proliferation. By revealing an unexpected systemic role for a gustatory receptor, our work expands the conceptual framework of nutrient sensing and suggests conserved principles by which metabolic state governs blood cell development across animals.
    Keywords:  fructose; gustatory receptor; hematopoiesis; nutrient sensing; polyamine
    DOI:  https://doi.org/10.1073/pnas.2535199123
  24. Cell Metab. 2026 Jun 10. pii: S1550-4131(26)00234-2. [Epub ahead of print]
    Gut microbiota and metabolic control of immune checkpoint blockade in cancer.
    Joseph L Gladstone, Gregory F Sonnenberg.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.008
  25. bioRxiv. 2026 Jun 03. pii: 2026.05.30.728988. [Epub ahead of print]
    Human Genome-Scale Models of Metabolism and Gene Expression Reveal Resource Constraints of Cancer Cell Lines.
    Hratch Baghdassarian, Pablo Di Giusto, Juan Tibocha-Bonilla, Erick Armingol, Saratram Gopalakrishnan, Leo Dworkin, Laurence Yang, Nathan E Lewis.
      Genome-scale metabolic models (M-models) provide mechanistic insight into intracellular metabolism by simulating fluxes subject to nutrient and energy resource constraints. However, they cannot account for a major component of resource allocation, since they do not explicitly account for the cost of producing and maintaining enzymes. Genome-scale models of metabolism and gene expression (ME-Models) address this by including gene expression reactions, but these have only been developed for prokaryotes due to the additional complexity and challenges of modeling eukaryotes. Here, we present the human ME-Model, which encodes transcription, translation, complex formation, and turnover reactions for all enzymes catalyzing metabolic reactions, and couples these processes to constrain metabolic fluxes. We introduce humanME, a Python package to build and analyze human ME-Models. With this, we constructed 16 cancer cell line ME-Models. We found that resource constraints improve growth-rate predictions, and that ME-Model flux predictions are more biologically plausible and efficient. Moreover, transcriptional fluxes recapitulate RNA-Seq expression levels, with discrepancies revealing potential trade-offs involving multiple cellular objectives. Finally, the ME-Model recapitulates the Warburg effect, with increasing growth rate inducing glycolytic shifts, in part due to machinery costs of the electron transport chain. Altogether, we show ME-modeling can mechanistically link gene expression, resource allocation, and metabolism in human cells, substantially expanding the predictive scope of constraint-based models.
    DOI:  https://doi.org/10.64898/2026.05.30.728988
  26. bioRxiv. 2026 Jun 03. pii: 2026.06.01.729220. [Epub ahead of print]
    Model-based inference of enzyme inhibitions from perturbation-induced metabolic dynamics.
    Wolfram Liebermeister, Michela Pauletti, Terézia Dorčáková, Caspar Rahm, Mattia Zampieri.
      In microbes, metabolism plays a key role in the first rapid adaptation to sudden challenges such as nutrient limitations or toxic compounds. While metabolomics enables the profiling of stimuli-induced metabolic changes, computational approaches that can interpret these data to mechanistically explain how perturbations propagate through metabolism to produce the observed changes are lagging behind. Here, we developed a computational framework, called Inference from Metabolic Fingerprints (IMF), to model the immediate dynamic response to a metabolic perturbation and systematically infer its entry point (i.e. enzymatic target). IMF assumes small perturbations and linearizes the nonlinear dynamics around a reference steady state. This allows IMF to scale with large metabolic networks and bypass missing kinetic parameters by allowing for fast and efficient ensemble sampling. We apply IMF to a model of central metabolism in Escherichia coli . Using in-silico and experimental data, we demonstrate the ability to infer the target of metabolic perturbations in spite of unknown kinetic parameters and incomplete metabolic data. Hence, we show that IMF is an effective approach for designing, analyzing and interpreting time-resolved metabolomics.
    DOI:  https://doi.org/10.64898/2026.06.01.729220
  27. Mol Cell. 2026 Jun 11. pii: S1097-2765(26)00323-0. [Epub ahead of print]
    SenCat: Cataloging human cell senescence through multi-omic profiling of multiple senescent primary cell types.
    Carlos Anerillas, Gisela Altés, Katarina Gresova, Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Reema Banarjee, Ana S G Cunningham, Martin Salamini-Montemurri, Jen-Hao Yang, Rachel Munk, Martina Rossi, Yulan Piao, Bradley Olinger, Quinn Strassheim, Jennifer L Martindale, Jinshui Fan, Chang-Yi Cui, Supriyo De, Delaney V Rutherford, Ying Hao, Ziyi Li, Jessica Roberts, Yue Andy Qi, Kotb Abdelmohsen, Rafael de Cabo, Allison B Herman, Manolis Maragkakis, Nathan Basisty, Myriam Gorospe.
      There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize senescent-cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed "SenCat." We found that while senescent cells from all primary cell types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Moreover, machine-learning-refined SenCat signatures enabled senescence scoring and identification across multiple human and mouse datasets, both at bulk and single-cell levels. In sum, SenCat represents a much-needed resource to identify senescence across multiple cell types and tissues in the body.
    Keywords:  aging; machine learning; mass spectrometry; proteomics; senolytics; senotype; single-nuclei RNA-sequencing; transcriptomics
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.017
  28. Nat Commun. 2026 Jun 12.
    Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
    Ou Jiang, Zichen Cao, Sihan Kong, Qibing Wu, Tianyi Zhang, Xinyue Chen, Bo Zhou, Yao Feng, Songyue Wu, Jinsong Wang, Mo Chen, Xiaoyu Li, Songlin Wang.
      White adipose browning is a promising route to restore energy balance; however, how inorganic anion signals engage intracellular organelle networks to drive this process remains unclear. Here, we identify Sialin2 as a nitrate sensor that converts dietary nitrate into a spatially confined thermogenic program by coupling ER-mitochondria Ca2+ transfer with lipid routing into mitochondrial oxidation. Sialin2 localizes to mitochondria and the endoplasmic reticulum (ER), where it strengthens ER-mitochondria contacts and engages the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit to enhance inducible mitochondrial Ca2+ uptake. In parallel, Sialin2 associates with lysosomal acid lipase (LIPA), acyl-CoA synthetase long-chain family member 3 (ACSL3), and carnitine palmitoyltransferase 1 A (CPT1A) to channel lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid cycle and uncoupling protein 1 (UCP1)-dependent respiration. Loss of Slc17a5 abolishes nitrate-evoked browning and metabolic benefits, whereas nitrate supplementation improves adipose thermogenesis and systemic metabolic indices in male mice with diet-induced obesity without adrenergic stimulation. Together, these findings identify an organelle-specific nitrate-sensing mechanism that couples inorganic anion signalling to substrate routing in adipocytes and establish a non-hormonal pathway for restoring metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74256-w
  29. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2601061123
    Hp1bp3 loss links chromatin reorganization to metabolic vulnerability in glioma.
    Brittney Lozzi, Taylor A Gatesman, Pushan Dasgupta, Debosmita Sardar, Yeunjung Ko, Chenyu Mao, Hsiao-Chi Chen, Rachel N Curry, Dongjoo Choi, Carrie A Mohila, Melissa L Bondy, Ganesh Rao, Marco Gallo, Sameer Agnihotri, Benjamin Deneen.
      High-grade gliomas (HGGs) are aggressive brain tumors with poor prognosis, driven in part by metabolic and epigenetic adaptations. Methionine metabolism supports HGG growth by supplying S-adenosylmethionine for methylation reactions, yet how nutrient availability influences chromatin organization in HGG remains incompletely understood. Using an immunocompetent mouse model of HGG, we found that dietary methionine restriction reduced tumor proliferation, extended survival, and induced partial nuclear inversion. We identified Hp1bp3 as a key regulator of tumor growth that functions by interacting with nuclear tethering proteins to mediate chromatin reorganization. Loss of Hp1bp3 results in the upregulation of histone demethylases leading to selective depletion of H3K9me3-marked heterochromatin and accelerated glioma growth. Combining methionine restriction with Hp1bp3 loss increased the frequency of partial nuclear inversion and further suppressed tumor progression. These findings identify Hp1bp3 as a chromatin regulator linking methionine metabolism to heterochromatin stability and suggest that dietary methionine modulation can influence the structural organization of chromatin to slow tumor growth in HGG.
    Keywords:  dietary restriction; epigenetics; glioma; methionine; nuclear organization
    DOI:  https://doi.org/10.1073/pnas.2601061123
  30. Cell. 2026 Jun 12. pii: S0092-8674(26)00640-9. [Epub ahead of print]
    Gregory J. Hannon (1964-2026).
    Julius Brennecke, Scott W Lowe.
      
    DOI:  https://doi.org/10.1016/j.cell.2026.05.040
  31. Nature. 2026 Jun 10.
    Mitochondria directly interact with the nuclear pore complex.
    Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.
      Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
    DOI:  https://doi.org/10.1038/s41586-026-10588-3
  32. Cell Stem Cell. 2026 Jun 09. pii: S1934-5909(26)00227-4. [Epub ahead of print]
    SPACE-seq integrates spatial transcriptomics and lineage tracing in native tissues.
    Yuemeng Jia, Dawei Sun, Jackson A Weir, Xugeng Liu, Andrew J C Russell, YeEun Kim, Nicholas Thom, Giovanni Marrero, Vipin Kumar, Fei Chen, Fernando D Camargo.
      Understanding how cells change state, interact with their neighbors, and organize into tissues requires recording of cellular lineage history in native spatial context. Here, we present SPACE-seq (spatial tracing enabled by CRISPR-based barcodes and slide-seq), a versatile platform that integrates CRISPR-based lineage recording with spatial transcriptomics to jointly resolve lineage, cell state, and tissue architecture at near-cellular resolution in situ. Using SPACE-seq, we uncovered intratumor transcriptional diversification among clonally related cells and identified tumor-stroma crosstalk that reciprocally reshapes behaviors of both malignant and stromal populations, which we further experimentally validated. Beyond disease, SPACE-seq revealed a narrow developmental window in which hepatoblast dispersion contributes to spatially confined lineage compartments that prefigure liver lobar architecture. Together, these results highlight the broad applicability and adaptability of SPACE-seq to uncover previously inaccessible principles of cellular organization, lineage dynamics, and tissue patterning.
    Keywords:  brain development; cellular barcoding; lineage tracing; liver cancer; liver development; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.stem.2026.05.017
  33. J Clin Invest. 2026 Jun 09. pii: e203835. [Epub ahead of print]
    Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.
    Rhea Sahu, Miriam Enos, Swastika Sharma, Amy E Schade, Alycia Gardner, Akiko Yoshinaga, Alexandra Indeglia, Eleanor Minogue, Songhua Hu, Kiran Kurmi, Shakchhi Joshi, Daniel R Schmidt, Samkyu Yaffe, Van Tm Nguyen, Fang Xie, Steven P Balk, Matthew G Vander Heiden, Kristian Helin, Marcia C Haigis, Karen Cichowski.
      Men with advanced prostate cancer are typically treated with androgen deprivation therapy, but most ultimately develop resistance and incurable disease (e.g. castration-resistant prostate cancer (CRPC)). The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing two targetable pathways outside of AR. Here we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation prior to cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting two key regulators of metabolism, MYC and HIF-1A, while concomitantly derepressing a pro-apoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by co-targeting upstream oncogenic nodes that converge on this important process.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology; Signal transduction; Therapeutics
    DOI:  https://doi.org/10.1172/JCI203835
  34. J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02116-2. [Epub ahead of print] 113244
    Mitochondrial permeability transition in redox homeostasis and ferroptosis.
    Lishu Guo.
      Mitochondria are major sources of intracellular reactive oxygen species (ROS), and act as central signaling hubs in maintaining homeostasis of cellular oxidative states. Mitochondrial permeability transition (MPT) is coordinately mediated by mitochondrial outer membrane permeabilization (MOMP) and opening of the permeability transition pore (PTP). MPT is highly sensitive to ROS, and serves as a critical checkpoint in redox balances and cell death. This review will summarize the regulatory systems of mitochondrial and intracellular redox homeostasis, as well as the recent advances in understanding of MPT regulatory mechanisms. Furthermore, this review highlights the functional roles of MPT in redox homeostasis and ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death. The PTP is a critical molecular switch, which can convert from a defender against mitochondrial redox stress and cell death processes, including specifically iron-dependent, lipid peroxidation-driven cell death, known as ferroptosis, into a ROS amplifier and cell death promoter depending on its open states. MOMP causes the uncoupling of the mitochondrial respiratory chain, and increases ROS production, leading to oxidative stress. The most recent work suggests that the interplay between MTCH2 and F-ATP synthase coordinates MOMP and the PTP opening to mediate the occurrence of MPT. This review provides insight on molecular switches that regulate MPT, determining redox state and cell death.
    Keywords:  ferroptosis; mitochondria; mitochondrial permeability transition; redox homeostasis; the permeability transition pore
    DOI:  https://doi.org/10.1016/j.jbc.2026.113244
  35. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2523043123
    LARP1 integrates MYC and mTOR signaling to enable anabolic growth during tumor initiation.
    Pedro Fuentes, Flavia Iannizzotto, Elisa Battaglia, Chiara Balzamo, Carla Tola, Berta Forcada, Pau Bosch-I-Crespo, Francisco D Morón-Duran, Brandon E Frank, Carolina Martínez-Herráez, Zoi Mastora, Gabriella Manfili-Marinho, Albert Tauler, Cristina Santos, Ramón Salazar, Antonio Gentilella.
      Tumor initiation requires the integration of oncogenic signals with environmental cues to enable anabolic growth. MYC is central to tumorigenesis, with its deregulation observed in over 60% of human cancers. Oncogenic MYC profoundly rewires transcription, enabling cells to bypass cell cycle checkpoints and reset metabolism. A cornerstone of this rewiring is the upregulation of biomass-producing pathways, particularly ribosome biogenesis. How and when MYC's oncogenic program is translationally executed-either immediately or until a favorable metabolic context emerges-remains a central unanswered question in tumor initiation, limiting our understanding of tumor latency and early intervention. Here, we identify LARP1 as a critical effector of MYC-driven transformation, connecting MYC oncogenic activity with mTOR signaling. Mechanistically, MYC represses miR-26a/b, relieving posttranscriptional repression of LARP1 and leading to its upregulation. LARP1 associates with the translational machinery, loading it with the anabolic translatome induced by MYC in a translationally poised state. Upon permissive mTOR signaling, and dependent on the phosphorylation of LARP1 at serines 689 and 697, this program is rapidly translated, fueling the biosynthetic processes essential for tumor development. Importantly, genetic deletion of LARP1 or pharmacological mTOR inhibition completely abrogates tumor initiation in a genetically engineered colorectal organoid model of MYC-driven tumorigenesis. This underscores the physiological relevance of this two-step mechanism in which LARP1 bridges the anabolic translatome primed by MYC with its metabolic execution controlled by mTOR. By temporally uncoupling transformation from metabolic permissiveness, this mechanism defines a critical checkpoint in early tumorigenesis, revealing a potential vulnerability for intercepting MYC-driven cancer before biomass expansion.
    Keywords:  MYC; mTOR; oncogenic translational program; tumor anabolism; tumor initiation
    DOI:  https://doi.org/10.1073/pnas.2523043123
  36. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  37. Nat Commun. 2026 Jun 12.
    Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
    Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.
      To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
    DOI:  https://doi.org/10.1038/s41467-026-74127-4
  38. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  39. Science. 2026 Jun 11. 392(6803): 1128-1129
    The placental metabolic clock.
    Kiyoshi Yoshioka, Shin-Ichiro Imai.
      NAD+ depletion triggers a countdown to birth in mice.
    DOI:  https://doi.org/10.1126/science.aei4119
  40. Nat Metab. 2026 Jun 09.
    Rise in sugar decoration in Alzheimer's disease.
    Yasuhiko Kizuka.
      
    DOI:  https://doi.org/10.1038/s42255-026-01531-x
  41. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00558-9. [Epub ahead of print]45(6): 117480
    The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2.
    Akito Tsuruta, Nodoka Hirao, Megumi Shibata, Yuya Yoshida, Yoshihiro Izumi, Naoya Shindo, Yuki Shiiba, Kazuhiro Higashi, Takuto Inoki, Yuichiro Kai, Yasuha Hiraoka, Tomoaki Yamauchi, Akio Ojida, Takeshi Bamba, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.
    Keywords:  BMAL1; CP: immunology; CP: metabolism; Intranuclear acetyl-CoA; MFP2; circadian rhythm; inflammation; peroxisomal β-oxidation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117480
  42. bioRxiv. 2026 Jun 06. pii: 2026.06.05.729624. [Epub ahead of print]
    Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling.
    Roseanne E Nooren, Katherine M Johnson, Maxwell G Marley, Cody N Rozeveld, Daniel F Gibbard, Zinnarky K Ortiz Correa, Mustafa Emre Gedik, Tianna Espe, Taro Hitosugi, Ian R Lanza, Douglas G Brownfield, Jun Liu, Mark A McNiven, Gina L Razidlo.
      Metabolic vulnerabilities in cancer have been targeted primarily to suppress tumor growth, but less is known about the metabolic requirements for tumor cell invasion. Here we report that lipid catabolism by cytosolic and lysosomal lipases supports pancreatic cancer cell invasion through both overlapping and distinct functional and metabolic mechanisms. Lysosomal acid lipase (LAL)-dependent lipid droplet catabolism promotes invadopodia formation and stabilization, enabling extracellular matrix degradation. In addition to modulating cellular energetics, lipidomics revealed that lipid droplet catabolism regulates cholesterol and membrane phospholipid levels. Using spatially resolved biosensors and cholesterol imaging, we found that lysosomal lipid catabolism occurs at invadopodia and sustains local ATP and membrane cholesterol. These findings identify spatially organized lipid catabolism as a mechanism that couples local energetics and membrane remodeling during the earliest steps of pancreatic cancer cell invasion.
    DOI:  https://doi.org/10.64898/2026.06.05.729624
  43. Cell. 2026 Jun 11. pii: S0092-8674(26)00587-8. [Epub ahead of print]189(12): 3501-3505
    Charting human cellular senescence in aging and disease.
    NIH SenNet consortium
      Cellular senescence comprises diverse cell states emerging across human tissues during aging and disease. Integrating single-cell and spatial multi-omics with AI-driven analyses enables systematic mapping of senescent cell heterogeneity ("senotypes"), revealing tissue-specific programs and microenvironmental interactions. These advances provide frameworks for biomarker discovery and development of targeted senotherapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.028
  44. bioRxiv. 2026 Jun 06. pii: 2026.06.05.730386. [Epub ahead of print]
    Vacuole pH loss triggers ESCRT-dependent plasma membrane remodeling to prevent amino acid toxicity.
    Kevin C Chui, Casey E Hughes, Troy K Coody, Adam L Hughes.
      Loss of lysosomal or vacuolar acidity is a hallmark of aging, metabolic dysfunction, and cellular stress, yet how cells adapt to this condition remains poorly understood. In budding yeast, where the vacuole serves as a major reservoir for intracellular amino acids, impaired vacuolar acidification disrupts amino acid homeostasis. Here we performed a genome-wide screen in budding yeast to identify pathways required for survival during vacuole pH stress. We found that endocytic trafficking and ESCRT/MVB components become essential when vacuolar acidification is disrupted. Vacuole deacidification triggered ESCRT-dependent rerouting and degradation of plasma membrane amino acid transporters, thereby limiting nutrient influx. Blocking this response stabilized transporters at the cell surface and caused synthetic lethality under vacuole stress. This growth defect was suppressed by lowering amino acid availability or reducing transporter expression, whereas amino acid supplementation restored toxicity. Nitrogen starvation prevented transporter internalization, indicating that nutrient status gates this adaptive response. Together, these findings reveal a vacuole-plasma membrane communication pathway that protects cells from amino acid toxicity by matching nutrient influx to vacuolar function.
    DOI:  https://doi.org/10.64898/2026.06.05.730386
  45. bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]
    Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
    Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.
      Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.
    DOI:  https://doi.org/10.64898/2026.06.04.730191
  46. J Cell Biol. 2026 Aug 03. pii: e202507165. [Epub ahead of print]225(8):
    Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages.
    Isabella M Gaeta, Shuangshuang Du, Clémentine Villeneuve, David G Gonzalez, Catherine Matte-Martone, Smirthy Ganesan, Deandra Simpson, Hilldana Tibebu, Jessica L Moore, Chen Yuan Kam, Sara Gallini, Haoyang Wei, Fabien Bertillot, Dagmar Zeuschner, Lauren E Gonzalez, Ushnish Rana, Kaelyn D Sumigray, Sara A Wickström, Valentina Greco.
      Regenerative organs, like the skin, depend on niche-stem cell interactions that sustain cellular turnover. In culture, skin fibroblasts promote epidermal stem cell proliferation and differentiation. Yet, it remains elusive how fibroblasts regulate epidermal stem cell behaviors and differentiation in vivo in skin. Here, we asked how fibroblast depletion may impact proliferation of the epidermal stem cell compartment. Surprisingly, we find that significant depletion of fibroblast density does not affect epidermal stem cell proliferation during adult or neonatal stages in vivo. These results demonstrate that across different ages, proliferation of epidermal stem cells can persist in the face of a depleted fibroblast population. Interestingly, neonatal fibroblast depletion does not significantly reduce collagen I density but affects basement membrane mechanics and epidermal stem cell delamination. Despite these changes, the skin continues to maintain its protective barrier function. Thus, our work demonstrates the skin regenerative program employs robust compensatory mechanisms in response to fibroblast depletion to maintain functional capacity.
    DOI:  https://doi.org/10.1083/jcb.202507165
  47. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00575-9. [Epub ahead of print]45(6): 117497
    STING dampens the unfolded protein response to enable the presentation of self-antigens on MHC-I during inflammation.
    Ahmed M Fahmy, Ali Ahmadi, Joël Lanoix, Tyler Cannon, Moustafa N Elemeery, Camberly Hernandez Paredes, Benoit Barrette, Eric Bonneil, Yong Zhong Xu, Maha Ibrahim, Guillermo Arango-Duque, Eric Olivier Audemard, Sébastien Lemieux, Eric Chevet, Erwin Schurr, Philippe Pierre, Samantha Gruenheid, Pierre Thibault, Heidi M McBride, Michel Desjardins.
      A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8+ T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is engaged through a pathway involving cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which acts as a rheostat to dampen the unfolded protein response (UPR). Without STING, the stress response is amplified, leading to a translational attenuation that inhibits the expression of XBP1s, a transcription factor required for MitAP. STING activity also regulates the repertoire of peptides displayed at the cell surface during inflammation, highlighting a potential role in immunosurveillance. These findings establish STING and the UPR as key immune regulators targetable for therapeutic intervention during autoimmune diseases and PD.
    Keywords:  CP: cell biology; CP: molecular biology; Parkinson’s disease; STING; UPR; antigen presentation; immunopeptidomics; immunosurveillance; inflammation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117497
  48. Nat Cancer. 2026 Jun 12.
    Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets.
    Clinical Proteomic Tumor Analysis Consortium
      Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematological malignancy. Here, to better define this clinically taxing and translationally challenging malignancy, we applied a multiomics approach, consisting of 13 modalities to analyze 173 treatment-naive individuals with AML. By integrating these 'omes', we identified distinct AML subtypes, genotype-phenotype associations, biomarkers and pathobiological mechanisms. Across the spectrum of primitive and committed AML, we found extensive metabolomic and lipidomic reprogramming driven by divergent MYC and mTOR activity. We linked metabolic changes to striking hyperacetylation of mitochondrial proteins in CEBPA-mutant AML. Protein-centric subtyping revealed a distinct NPM1-mutant subset characterized by outlier expression of FOXC1 and HOXB8/9. To nominate therapeutic targets across subtypes, we developed a multiomic machine-learning approach and validated MTA1 as a contributor to panobinostat resistance. Altogether our findings underscore the complex nature of AML and provide a clinically and translationally informed unified view that reveals coalescent phenotypes across multiomic layers.
    DOI:  https://doi.org/10.1038/s43018-026-01175-6
  49. Science. 2026 Jun 11. eadv8291
    Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
    Eve Kandyba, Arnaud Jabouille, Ferriol Calvet, Yun Rose Li, Andrea Curtabbi, Diana Cristea, Joyce Shin, Reyno Delrosario, Jonathan Anzules, Di Wu, David Quigley, Mark Taylor, Camila Zanette, Fang Yin Lo, Jacob Higgins, Jesse Salk, Nuria Lopez-Bigas, Allan Balmain.
      The identification of the cancer cell of origin is a fundamental question in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single cell transcriptomics, and Duplex sequencing, to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and / or Lrig1+ stem cells of the upper hair follicle, but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded, but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between Hras and Kras pathways that influences clonal selection.
    DOI:  https://doi.org/10.1126/science.adv8291
  50. Redox Rep. 2026 Dec 31. 31(1): 2687238
    Significance of GSH and H2S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health.
    Avisek Majumder, Suravi Majumder, Shabana Bano, Koushik Sen, Kasturi Bala Nayak.
      Due to the proliferative nature of cancer cells, they utilize more dietary extracellular nutrients via one-carbon metabolism for the various metabolic processes, including the synthesis of antioxidants such as glutathione (GSH) and hydrogen sulfide (H2S). Indeed, several studies have found that specific cancer types produce significantly higher levels of GSH and H2S than normal healthy cells, which may serve as a protective mechanism, allowing them to resist stress, survive, and grow. This metabolic heterogeneity, driven by intrinsic and extrinsic factors, contributes to the distinct metabolic characteristics and vulnerabilities of tumor subtypes, which can be exploited to develop anticancer strategies. In this review, we summarize the fundamental roles and regulation of GSH and H2S in normal physiological systems and in the genesis and progression of cancer, their effects on the tumor microenvironment (TME), and their contribution to drug resistance. We also discuss the influences of diet and the gut microbiome on GSH and H2S production, and how cancer cells reprogram their metabolism to grow and survive in a stressful environment by overproducing GSH and H2S.
    Keywords:  Persulfide; ferroptosis; gut microbiome; immunotherapy; lipid peroxidation; methionine restriction; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.1080/13510002.2026.2687238
  51. EMBO Rep. 2026 Jun 08.
    L-type voltage-gated Ca2+ channels control T cell killing via non-canonical Hedgehog signalling.
    Flavio Beke, Joachim Hanna, Chrysa Kapeni, Valentina Carbonaro, Nico Mueller, Sophie Trotter, Chandra Chilamakuri, Louise M O'Brien, Maike de la Roche.
      Cytotoxic CD8+ T lymphocytes (CTLs) efficiently eliminate infected and cancerous cells throughout the body. T cell receptor (TCR)-induced Hedgehog signalling contributes to CTL-mediated killing, but how the pathway is activated downstream of the TCR is unknown. Here, we show that extracellular calcium (Ca2+) flux through L-type voltage-gated Ca2+ (Cav1) channels at the plasma membrane downstream of the TCR drives induction of the Hedgehog transcription factor Gli1, which is important for CTL killing in vitro and in vivo. This previously unknown non-canonical Hedgehog pathway is independent of canonical signalling and represents a primary mechanism of Gli1 induction in naive CD8+ T cells, whereas CTLs can also activate Gli1 via MAPK. We further show that Cav1 channel-controlled Gli1 induction is functionally important for CTL killing in mice and humans and other cytotoxic lymphocytes. Notably, killing capacity can be amplified using a small molecule Cav1 agonist or by overexpressing a gain-of-function Cav1 subunit. These findings suggest a strategy to improve cytotoxic lymphocyte function in the clinic, including in CAR T cell therapy.
    DOI:  https://doi.org/10.1038/s44319-026-00810-8
  52. J Natl Cancer Cent. 2026 Jun;6(3): 211-218
    Intrinsic and extrinsic regulators of cancer dormancy and awakening.
    Jingwei Zhang, Md Imtiaz Khalil, Ranjan Mishra, Hao Li, Luigi Perelli, Robert A Weinberg.
      Metastatic relapse is frequently driven by dormant disseminated tumor cells (DTCs) that previously evaded initial therapy, disseminated to distant tissues, entered into a non-proliferative state termed dormancy, and later reawakened to reinitiate active proliferation and the outgrowth of macroscopic metastases. Cancer dormancy manifests itself in two principal forms: cellular dormancy, characterized by the reversible, proliferative quiescence of individual cells, and tumor mass dormancy, defined by a balance between proliferation and compensating cell death. Dormant cells are notably resistant to conventional therapies and immune-mediated clearance, yet retain viability and the potential to re-enter the active cell cycle. The present review focuses on dormancy of DTCs residing in distant tissues and highlights recent advances in our understanding of both cell-intrinsic and -extrinsic regulators of cancer dormancy. Key cell-autonomous mechanisms include ERK/p38 signaling ratios, epithelial-mesenchymal plasticity, and Wnt signaling. At the same time, signals received by dormant DTCs from the adjacent tissue microenvironment-such as TGF-β family cytokines, immune surveillance, and other stromal interactions-induce and sustain dormancy. Importantly, emerging evidence suggests that microenvironmental conditions, including inflammation and aging, can trigger the awakening of dormant DTCs, leading to metastatic outgrowth. We review these evolving insights into the molecular and environmental control of cancer dormancy and awakening, underscoring their clinical relevance and therapeutic potential in preventing metastatic recurrence.
    Keywords:  Cancer dormancy and awakening; Disseminated tumor cells; Epithelial-mesenchymal plasticity; Metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jncc.2026.03.007
  53. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00585-1. [Epub ahead of print]45(6): 117507
    Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
    Kaja Plucińska, Charlotte R Wayne, Henry Sanford, Boby Mathew, Nathalie Ropek, Stephanie M Adaniya, Corey Model, Nicolás Gómez-Banoy, Ksenia Morozova, Xiongwen Cao, Jeffrey M Friedman, Ken H Loh, Paul Cohen, Ekaterina V Vinogradova.
      Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we develop a method enabling temporally controlled, cell-type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. The expression of TurboID in hepatocytes, adipocytes, and B lymphocytes enabled the characterization of cell type-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue- and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy balance and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.
    Keywords:  CP: metabolism; ER proteomics; TurboID; inflammation; obesity; plasma proteomics; proximity labeling
    DOI:  https://doi.org/10.1016/j.celrep.2026.117507
  54. Autophagy. 2026 Jun 12. 1-3
    Cell stress and death liberate the autophagy-inhibitory tissue stress hormone DBI/ACBP into the circulation.
    Yan Rong, Flavia Lambertucci, Yaning Yang, Yanbing Dong, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer.
      Autophagy constitutes a major adaptive response that preserves cellular and organismal homeostasis during stress. However, stress responses also engage systemic communication pathways that may either maintain resilience or propagate pathology. We previously identified acyl-CoA-binding protein, also known as diazepam-binding inhibitor (DBI/ACBP), as a phylogenetically conserved extracellular factor secreted by stressed cells through an unconventional autophagy-dependent pathway. Once released, extracellular DBI/ACBP acts as a feedback inhibitor of autophagy and promotes metabolic and inflammatory alterations. In our most recent work, we identify regulated cell death as an additional major mechanism responsible for extracellular DBI/ACBP accumulation. Plasma DBI/ACBP concentrations correlate with markers of inflammation, senescence and multiorgan dysfunction in hospitalized patients. Experimentally induced injury to liver, kidney, pancreas or skeletal muscle indistinguishably causes rapid increases in circulating DBI/ACBP. Mechanistically, apoptosis, ferroptosis and necroptosis all provoke loss of intracellular DBI/ACBP together with its extracellular release following plasma membrane permeabilization. Pharmacological inhibition of these death pathways suppresses DBI/ACBP liberation. Across large human cohorts, elevated plasma DBI/ACBP is associated with aging, systemic inflammation, multiorgan dysfunction and future morbidity. We propose that DBI/ACBP is not merely a biomarker of tissue damage but rather a systemic autophagy-inhibitory stress signal contributing to maladaptive interorgan communication during aging and disease.
    Keywords:  Aging; disease; mortality; organ failure; stress
    DOI:  https://doi.org/10.1080/15548627.2026.2685761
  55. Nature. 2026 Jun 10.
    Mutation-dependent responses to sleep and exercise in clonal haematopoiesis.
    Teresa Gerhardt, Walter Jacob, Lena Gaebel, Merlin Heiser, Christopher Wolfram, Pacific Huynh, Tetsushi Nakao, Bernardo Gindri Dos Santos, Pamela Toh, Aaron Douglas, Niki F Brisnovali, Emir Radkevich, Md Mesbah Uddin, Abi G Yates, Annie Khamhoung, Nader Yatim, Matteo Gianeselli, Máté G Kiss, Sukanya Goswami, Daniella Nelson, Rachel Chen, Darwin D'Souza, Zhihong Chen, Seunghee Kim-Schulze, Trevor Fidler, Daniel Ezzat, Shaan Khurshid, Alexander G Bick, Pradeep Natarajan, Patrick T Ellinor, Abha K Rajbhandari, Miriam Merad, Filip K Swirski, Oren Cohen, Leigh Goedeke, Michael C Honigberg, Cameron S McAlpine.
      Clonal haematopoiesis (CH) activates inflammation and increases the risk of atherosclerosis1,2. Whether lifestyle alters CH clone expansion or the phenotypic programming of CH mutant cells, thereby affecting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, Trp53 and Dnmt3a, we demonstrate mutation-dependent responses to sleep and exercise in CH and show that mutant cells are uniquely sensitive to lifestyle. In two human datasets, moderate-to-vigorous physical activity was associated with lower prevalence of non-DNMT3A-driven CH. In atherogenic mice with Jak2V617F or Tet2 loss of function (LOF), but not Trp53 LOF or Dnmt3aR878H CH, uninterrupted sleep or exercise curtails clone expansion. In CH with the Jak2V617F mutation, sleep and exercise reduces clone expansion by selectively reprogramming mutant, but not cohabitant wild type, haematopoietic progenitor cells towards antiproliferative and metabolically healthy phenotypes by tempering bone marrow macrophage-haematopoietic progenitor cell IL-1β signalling. Sleep or exercise also lessens Jak2V617F-driven, Tet2 LOF-driven and Trp53 LOF-driven, but not Dnmt3aR878H-driven, atherosclerosis by locally reprogramming mutant vascular macrophages, independent of peripheral clone dynamics. In Jak2V617F, but not adjacent wild type, aortic macrophages, uninterrupted sleep blunts CLEC4E-dependent inflammasome activation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the locus coeruleus, raising the levels of peripheral noradrenaline, which signals through adrenergic receptor β2 (ADRβ2) whose expression is preserved by exercise in Jak2V617F, but not cohabitant wild type, aortic macrophages, selectively repressing their inflammatory programming and atherosclerosis. Our findings establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant haematopoietic progenitor cells and macrophages to maintain cardiovascular health.
    DOI:  https://doi.org/10.1038/s41586-026-10634-0
  56. Nat Commun. 2026 Jun 11.
    Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
    Liang Shi, Boqiang Liu, Ruya Sun, Jing He, Hao Shen, Weiqi Li, Yi Wang, Weijun Zhao, Chenqi Jin, Binghan Jin, Yuanshi Tian, Lingfeng Ma, Lidan Hou, Mingyu Chen, Jiaying Shen, Bo Shen, Xiao Liang, Hong Yu, Yifan Wang, Di Wang, Xiujun Cai.
      Tumor evolution enables liver cancer cells to acquire survival advantages and evade therapy-induced cell death. However, the role of natural killer (NK) cells in liver cancer evolution remains unclear. Here, we establish immune-humanized spatiotemporal liver cancer models and integrate single-cell, spatial transcriptomic, and CRISPR/Cas9 screening analyses to investigate this process. We demonstrate that early NK cell-mediated immunosurveillance promotes tumor cell state transition and impairs subsequent adaptive immune responses. Mechanistically, NK cells induce lipid metabolic reprogramming, particularly cholesterol accumulation, and enhance tumor stemness, both of which promote liver cancer evolution. Furthermore, combined anti-LAG-3 treatment and liver X receptor activation suppress tumor evolution and improve the efficacy and durability of immune checkpoint blockade in advanced liver cancer. Collectively, our findings identify that NK cell-mediated early immunosurveillance promotes liver cancer evolution and suggest immunometabolic therapy as a potential strategy for advanced liver cancer.
    DOI:  https://doi.org/10.1038/s41467-026-74360-x
  57. Nature. 2026 Jun 08.
    Targeting Cancer-Specific Mutations with RNA-Triggered Chromatin Shredding.
    Jingkun Zeng, Zhiyuan Cheng, Huadong Chen, Zhaojun Wang, Jared Thompson, Kadin T Crosby, Hesong Han, Arushi Singhal, Wayne Ngo, Chenglong Xia, Daniel Rosas-Rivera, Zeyuan Zhang, Min Hyung Kang, Ying Mao, Morgan E Diolaiti, Giselle C Lee, John F X Diffley, Yixuan Song, Longhui Qiu, Nathan M Krah, Niren Murthy, Ryan N Jackson, Yang Liu, Alan Ashworth, Jennifer A Doudna.
      Genetic mutations that drive cancer often occur in tumor suppressor proteins, including the p53 transcription factor which is altered in ~40-50% of cases1,2. However, current therapies fail to target most such mutations because the mutant proteins typically lack defined drug-binding pockets, and restoring the endogenous function has proven challenging. Here, we programmed CRISPR-Cas12a2, an RNA-guided nuclease with trans-nucleolytic cleavage activities3,4, to selectively kill cancer cells by targeting cancer-specific transcripts. This approach limits cell growth by inducing trans shredding of chromatin, triggering DNA damage responses and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides a new approach to precision disease treatments for undruggable targets.
    DOI:  https://doi.org/10.1038/s41586-026-10738-7
  58. Nat Commun. 2026 Jun 08.
    Single-cell whole-genome sequencing reveals convergent evolution in Burkitt lymphoma.
    Alexander S Steemers, Markus J van Roosmalen, Rico Hagelaar, Laurianne Trabut, Mark Verheul, Jurrian K de Kanter, Siem Jongsma, Lucca L M Derks, Alexander R Blackwell, Friederike Meyer-Wentrup, Ruben van Boxtel.
      Burkitt lymphoma carries multiple oncogenic drivers yet arises predominantly in children, whose normal cells harbour few age-related mutations. To investigate this paradox, we seek to define the sequence and timing of mutational drivers underlying Burkitt lymphoma development. Here, we analyse single-cell whole-genome sequencing data of 250 paired normal and malignant B-cells from Burkitt lymphoma patients and integrate this data with 21 bulk WGS samples and an existing dataset of 157 clonally expanded B-cells from healthy individuals. Phylogenetic reconstruction reveals an accelerated accumulation of mutations following the emergence of the most recent common ancestor, leading to the early establishment of extensive genetic intratumoural heterogeneity. We further provide evidence that convergent evolution shapes this diversity at both the point mutation- and copy number variation-levels. This in-depth characterisation further establishes Burkitt lymphoma as a paradigmatic model of tumorigenesis with implications for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-74121-w
  59. Immunity. 2026 Jun 09. pii: S1074-7613(26)00217-7. [Epub ahead of print]59(6): 1481-1483
    Guardian of two galaxies: Senescence-associated immune cells control disease tolerance and aging.
    Wolfgang Vivas, Sebastian Weis.
      Preservation of host fitness is a common feature of longevity and immunity to infection. In this issue of Immunity, Triana-Martinez et al. reveal that p16High senescence-associated immune cells promote disease tolerance and healthy aging. Mechanistically, this is dependent on Toll-like receptor 7 (TLR7) and stimulator of interferon genes (STING) innate immune signaling controlling adenosine concentrations.
    DOI:  https://doi.org/10.1016/j.immuni.2026.05.006
  60. bioRxiv. 2026 Jun 07. pii: 2026.06.03.729837. [Epub ahead of print]
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Ushodaya Mattam, Omar Chaudhry, Karleigh G Porter, Saanvi Maadaadi, Dina Secic, Megan Bischoff, Karthickeyan Chella Krishnan, Rhett Kovall, Tom Cunningham, Maria Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.
    DOI:  https://doi.org/10.64898/2026.06.03.729837
  61. EMBO J. 2026 Jun 09.
    A DNA damage-activated kinase phosphorylates a transcriptional repressor to control bacterial immune pathway expression.
    Lydia R Chambers, Phoolwanti Rani, Ryan K Min, Elizabeth Villa, Kevin D Corbett.
      Bacteria encode numerous stress-response pathways that protect their hosts against both internal and external threats. A key question is how these pathways are regulated, especially anti-phage immune pathways that mediate host-cell killing. Here, we identify two proteins termed CapK and CapS that are encoded upstream of diverse immune operons, and regulate these operons' expression in response to DNA damage. CapK resembles bacterial anti-sigma factor kinases, and CapS resembles STAS-domain antagonists of these proteins. CapS is a DNA-binding transcriptional repressor, and phosphorylation of CapS by CapK results in dissociation of a CapS homodimer and de-repression of transcription. The CapK kinase is directly activated by single-stranded DNA generated as a byproduct of DNA repair. Finally, we show that CapK and CapS-like proteins have been co-opted into an anti-phage toxin-antitoxin system with a VapC-like protein, where they similarly respond to DNA damage to activate VapC nuclease activity. Overall, our results reveal how a kinase-substrate pair can regulate expression of an adjacent operon in response to DNA damage, and highlight the modularity of immune and other stress-response pathways.
    DOI:  https://doi.org/10.1038/s44318-026-00831-y
  62. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00598-X. [Epub ahead of print]45(6): 117520
    Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
    Ankita Shrivastava, Eric Nels Pederson, Trang Uyen Nguyen, Jacky Chuen, Prathibha Mohan, Shivangi Pande, Ana Ruiz Toribio, Nicolas Lecomte, Jerry Melchor, John C McAuliffe, Paul M Grandgenett, Vinagolu K Rajasekhar, Kaila Nishikawa, Anna Knörlein, Yael David, Ian M Willis, Christine A Iacobuzio-Donahue, Zhengqing Ouyang, Kamini Singh.
      Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.
    Keywords:  CP: cancer; CP: molecular biology; EEF1A; EIF4A; KRAS inhibitors; Ribosome; mRNA translation; mTOR signaling; mutant KRAS; oncogenic signaling; ribosome profiling; ribosome stalling, pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117520
  63. Nat Commun. 2026 Jun 13.
    In situ reprogramming of CAR-alveolar macrophages via liposomal nanomedicine for lung cancer immunotherapy.
    Hui Li, Chaoyi Lyu, Xiaoyao Cai, Yufeng Zhang, Qian Guo, Yanbin Chen, Cuihong Yang, Zujian Feng, Yumin Zhang, Jianfeng Liu.
      Immunotherapy has revolutionized lung cancer treatment; however, response rates remain suboptimal. Alveolar macrophages (AMs) within the tumor microenvironment contribute to immunotherapy resistance by inhibiting T cell function through metabolic exhaustion, as well by promoting tumor progression via a pro-tumor M2-like phenotype. Here, we describe a precision-engineered, cascade-targeted liposomal nanomedicine (pCAR-P3/LNP) that enables in situ reprogramming of AMs via a multi-step targeting strategy-including lung accumulation via intrapulmonary nebulization, active cellular targeting, and promoter-driven activation-to generate functionally optimized chimeric antigen receptor-expressing AMs (CAR-AMs). The CAR-AMs mediate synergistic antitumor efficacy through three integrated mechanisms: targeted phagocytosis of lung cancer cells, enhanced antigen presentation, and M1-like repolarization. Furthermore, CAR-AM-induced immune activation and memory potentiate the efficacy of immune checkpoint inhibitors and suppress metastatic progression in lung cancer models in female mice. This nanomedicine-based cell reprogramming strategy provides an approach to overcome immunosuppressive barriers in lung cancer immunotherapy and exemplifies the convergence of nanotechnology with immunology for enhanced therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41467-026-74162-1
  64. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  65. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00605-4. [Epub ahead of print]45(6): 117527
    Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer.
    Leonor Nunes Rodrigues, Hafsa Munir, Ibone Thate Arrazola, Matthias M Gaida, Christoph Eckert, Jerome Boulanger, Ana C F Ferreira, Andrew N J McKenzie, Jacqueline D Shields.
      Natural killer (NK) cells are cytotoxic innate lymphoid cells which directly kill tumor cells, thus represent an attractive target for immunotherapy. However, NK cells face immunosuppression in the tumor microenvironment (TME), rendering them dysfunctional. While cancer-associated fibroblasts (CAFs) represent an abundant, heterogeneous component of pancreatic ductal adenocarcinoma (PDAC), their interplay with NK cells is largely understudied. Analyzing human samples and employing mouse models of PDAC and functional assays, we observed that intratumoral NK cells are immature, and TGF-β driven myofibroblastic (my)CAFs are strong NK suppressors, in contrast to inflammatory (i)CAF. Furthermore, myCAF-enriched tumor areas excluded NK cells, consistent with their reduced capacity to attract NK cells. Pancreatic CAFs in general reduced NK cell cytotoxicity by direct contact and via soluble factors, including prostaglandin E2 (PGE2). This work reveals distinct and overlapping roles of CAF subpopulations on NK cell functions, suggesting that overcoming CAF-imposed barriers to NK cytotoxicity and tumor infiltration is essential to unleash their anti-tumoral properties.
    Keywords:  CAF; CP: cancer; CP: immunology; NK cells; PDAC; PGE2; fibroblasts; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117527
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 5:24.