bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–04–26
48 papers selected by
Christian Frezza, Universität zu Köln
  1. Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.
  2. Proteolytic control of mitochondrial protein translocases.
  3. Mitochondrial respiration supports cancer growth independent of OXPHOS.
  4. TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
  5. Microbiota-derived metabolites as modulators of cancer immunotherapy response.
  6. Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
  7. Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
  8. Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.
  9. Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains.
  10. Ubiquitination of glycogen and metabolites in cells and tissues.
  11. Structure-informed deep generation enables de novo metabolite annotation in untargeted metabolomics.
  12. Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment.
  13. Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.
  14. Ferroptosis surveillance: Insights from in vivo contexts.
  15. Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
  16. Measuring eating patterns in real life reveals high variability in timing and choices.
  17. LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
  18. Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
  19. Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.
  20. Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
  21. Fasting and Caloric Restriction Activate an ADIOL-NHR-91-Kynurenine Pathway Signaling Axis to Promote Healthspan.
  22. Heterogeneity and plasticity of cancer-associated fibroblasts.
  23. Senescent cell heterogeneity: origins, detection, and therapeutic implications.
  24. Polyamine homeostasis in Caenorhabditis elegans relies primarily on transport.
  25. Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
  26. Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
  27. Fast & fuelious: the malate-aspartate shuttle in brown adipocyte lipid metabolism.
  28. Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
  29. Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
  30. Glycerol-driven TNAP activation in thermogenesis and mineralization.
  31. Local cues, local killers: human natural killer cells across tissues.
  32. Early fibrotic niches establish tumour-permissive microenvironments.
  33. Energy constraint on human health.
  34. A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
  35. Structure-guided optimization of SLC1A1/EAAT3-selective inhibitors targeting renal cancer metabolism.
  36. Targeting RuvBL1 disrupts mitochondrial metabolism and structure in hepatocellular carcinoma.
  37. SPNS2 exports sphingosine-1-phosphate and imports glucose.
  38. The regulation, function and disease relevance of cytoplasmic tRNAs.
  39. 2'3'-cGAMP-induced membrane shearing promotes broad antiphage immunity.
  40. Cancer signaling beyond the genes.
  41. A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
  42. Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.
  43. Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice.
  44. Disruption of the SAGA CORE triggers collateral degradation of KAT2A.
  45. mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
  46. Focal white matter lesions drive grey matter inflammation and synapse loss.
  47. Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking.
  48. Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
  1. Nat Commun. 2026 Apr 18.
    Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.
    Ting Miao, Ying Liu, Mujeeb Qadiri, Amaury Dasseux, John M Asara, Yanhui Hu, Xiaomei Sun, Luz Del Carmen Pliego-Alcántara, Christian C Dibble, Norbert Perrimon.
      Coenzyme A (CoA), derived from Vitamin B5 (VB5; also called pantothenate), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well-characterized, much less is known about its tissue‑specific regulation and systemic physiological roles. Here, using Drosophila melanogaster, we uncover a gut-renal circuit in which dietary VB5 fuels CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non‑autonomously impacting gut homeostasis. We show that, in the MTs, Myc boosts renal CoA production by directly upregulating the pantothenate kinase Fbl (human PANK1-3 ortholog) and downregulating CG5828, which we characterize as the functional ortholog of the metabolite phosphatase and CoA synthesis suppressor PANK4 (dPANK4). Elevated CoA biosynthesis enhances mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter‑organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.
    DOI:  https://doi.org/10.1038/s41467-026-71716-1
  2. Protein Sci. 2026 May;35(5): e70553
    Proteolytic control of mitochondrial protein translocases.
    Lara Kroczek, Thomas Langer.
      Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.
    Keywords:  mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control
    DOI:  https://doi.org/10.1002/pro.70553
  3. Biochim Biophys Acta Rev Cancer. 2026 Apr 17. pii: S0304-419X(26)00065-X. [Epub ahead of print] 189593
    Mitochondrial respiration supports cancer growth independent of OXPHOS.
    Christos Chinopoulos.
      Oxidative phosphorylation is a coordinated process yielding ATP, yet its constituent modules can operate autonomously and support oxygen-dependent, non-OXPHOS reactions that serve cellular proliferation, including neoplasia. Furthermore, even with oxygen present and ETC active, ATP synthesis requires surpassing defined thresholds; thus, respiration is not equivalent to phosphorylation. This review surveys mitochondrial pathways that use the ETC with oxygen as the terminal electron acceptor yet decouple respiration from ATP synthesis. These pathways support tumor progression by sustaining mechanistically distinct respiration-supported currencies, states, and signals, including oxidized coenzyme Q, matrix NAD+, mitochondrial membrane potential, transhydrogenase-derived NADPH, the downstream oxidizing capacity of the CIII-cytochrome c-CIV segment, and ROS as context-dependent outputs. These determinants shape de novo purine and pyrimidine biosynthesis, one‑carbon metabolism, shuttling of reducing equivalents, heme and FeS biogenesis, and proline, choline, and sulfide metabolism, revealing targetable nodes in the respiratory redox network. Therapeutic progress is expected from interventions that collapse the underlying infrastructure - particularly at the coenzyme Q-junction and the CIII-cytochrome c-CIV segment - rather than from strategies aimed solely at ATP deprivation.
    Keywords:  Metabolic rewiring; Nucleotide biosynthesis; Oncometabolism; One‑carbon metabolism; Redox homeostasis; Respiratory chain; Tumor metabolism; Ubiquinone; electron transport chain
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189593
  4. JCI Insight. 2026 Apr 23. pii: e199449. [Epub ahead of print]
    TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
    Fei Li, Niv Vigder, David R Ziehr, Mari Kamiya, Hung N Nguyen, Diana E Ferreyra Faustino, Aseel H Khalil, Hilaire C Lam, Matthew L Steinhauser, Edy Y Kim, William M Oldham.
      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor-β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine-glutamate-α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease. .
    Keywords:  Amino acid metabolism; Cell biology; Fibrosis; Metabolism; Metabolomics; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.199449
  5. Nat Commun. 2026 Apr 21.
    Microbiota-derived metabolites as modulators of cancer immunotherapy response.
    Catherine Toner-Bartelds, Iris L Mimpen, Miguel Parra-Martinez, Boudewijn M T Burgering, Emile E Voest.
      The microbiome is a key regulator of host homeostasis and immune activity, in part through the production of metabolites. These microbiota-derived metabolites can modulate both the innate and adaptive immune system, as well as directly target tumour cells, thereby regulating anti-tumour immunity and response to immunotherapy. Here, we describe the current mechanistic knowledge on how these metabolites exert their effects and outline the methodologies used to detect and assess these metabolites. Finally, we summarize microbiota-targeted therapies capable of improving microbial functionality to ultimately enhance immunotherapy responses and improve patient survival.
    DOI:  https://doi.org/10.1038/s41467-026-72178-1
  6. Nat Commun. 2026 Apr 18. pii: 3589. [Epub ahead of print]17(1):
    Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
    Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari, Ulas Isildak, Pol Alonso-Pernas, Isabela Santos Valentim, Fengting Su, Lilia Espada, Melike Bayar, Li Fu, Andreas Koeberle, Handan Melike Dönertaş, Maria A Ermolaeva.
      Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.
    DOI:  https://doi.org/10.1038/s41467-026-71508-7
  7. Cancer Res. 2026 Apr 21.
    Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
    Mitchell E Fane, Daniel J Zabransky.
      Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1612
  8. Nat Cell Biol. 2026 Apr 24.
    Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.
    Mariantonietta D'Ambrosio, Matthew E H White, Efthymios S Gavriil, Laura Bousset, Jodie Birch, Aleksandra Gruevska, Emiliano Pasquini, Manuel Colucci, Winnie Fong, Simone Mosole, Aurora Valdata, Dimitris Veroutis, Katie Tyson, Vikas Ranvir, Sandra Prokosch, Joaquim Pombo, Aoki Ardisson, Sanjay Khadayate, George Young, Alex Montoya, Georgia Roumelioti, Jack Houghton, Jianan Lu, Pavel V Shliaha, Elena De Vita, Santiago Vernia, Vassilis G Gorgoulis, Suchira Gallage, Mathias Heikenwälder, Zoe Hall, Andrea Alimonti, Iain A McNeish, Edward W Tate, Jesús Gil.
      Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.
    DOI:  https://doi.org/10.1038/s41556-026-01921-z
  9. Nat Commun. 2026 Apr 21. pii: 3653. [Epub ahead of print]17(1):
    Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains.
    Amit Kumar Sahu, Alberto Minetti, Domenico Di Fraia, Antonio Marino, Patrick Rainer Winterhalter, Daniela Giustarini, Ranieri Rossi, Andreas Simm, Francesco Neri, Federico Galvagni, Christoph Gerhardt, Thorsten Pfirrmann, Alessandro Ori.
      The ubiquitin-proteasome system is essential for neuronal proteostasis, yet its function declines with age. How aging affects deubiquitylating enzymes (DUBs) in the vertebrate brain remains unclear. Here we used activity-based proteomics to profile cysteine protease DUBs in aging mouse and killifish brains. We identified a subset of DUBs that progressively lose catalytic activity with age despite stable protein abundance. Mechanistically, oxidative stress impaired DUB function through thiol oxidation, whereas antioxidant treatment with N-acetylcysteine ethyl ester (NACET) restored activity in aging brains. In human iPSC-derived neurons, global DUB inhibition and targeted inhibition of USP7, one of the most strongly age-affected DUBs, partially recapitulated ubiquitylation changes observed in aged brains. Temporal analysis in mice further revealed that DUB inhibition precedes proteasome decline during brain aging. Together, these findings identify redox-sensitive DUBs that lose activity with age and suggest impaired deubiquitylation as an early, potentially reversible driver of proteostasis decline in the aging brain.
    DOI:  https://doi.org/10.1038/s41467-026-71921-y
  10. Nature. 2026 Apr 22.
    Ubiquitination of glycogen and metabolites in cells and tissues.
    Marco Jochem, Simon A Cobbold, Craig A Goodman, Catharina Kueng, Anthony Cerra, Laura F Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S Wang, Simon R Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M Devine, Martin Brzozowski, Yuri Shibata, Niall D Geoghegan, Catriona A McLean, Bernhard C Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander.
      Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.
    DOI:  https://doi.org/10.1038/s41586-026-10548-x
  11. Nat Commun. 2026 Apr 20.
    Structure-informed deep generation enables de novo metabolite annotation in untargeted metabolomics.
    Hongmiao Wang, Haosong Zhang, Zheng-Jiang Zhu.
      Metabolite annotation, especially the discovery of unknown metabolites, remains a fundamental challenge in mass spectrometry-based untargeted metabolomics due to limited reference mass spectra. Here we present MetGenX, a structure-informed encoder-decoder neural network that enables efficient and controllable generation of metabolite structures directly from MS2 spectra. By reformulating the spectrum-to-structure task as a structure-to-structure generation problem, MetGenX significantly improves generation accuracy and chemical space coverage. In independent tests, it achieved top-1 accuracy of 55.9% on 1388 NIST MS2 spectra and 68.5% on 1681 spectra from real biological samples, outperforming existing in silico tools. Its structure-informed design ensures robust performance across both positive and negative ionization modes without retraining. Applying a multi-step annotation workflow to mouse liver untargeted metabolomics data, MetGenX identified two previously uncharacterized metabolites absent from major human metabolome databases. These results demonstrate MetGenX's strong potential to advance de novo metabolite annotation and facilitate the discovery of uncharacterized chemical entities.
    DOI:  https://doi.org/10.1038/s41467-026-72149-6
  12. Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00381-5. [Epub ahead of print]45(5): 117303
    Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment.
    Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Rachael L Field, Tran H Nguyen, Quazim A Alayo, Christopher G Huckstep, Barbora Vander Wielen, Jonathan R Brestoff, Sheila A Stewart, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov.
      Aging strongly impacts CD8+ T cells, including the loss of naive cells and the emergence of age-associated GZMK+CD8+ T cells (TAA cells). Although TAA cells constitute a major population in aged mice, the pathway underlying their differentiation remains unknown. Here, we demonstrate that TAA cell development is cell extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a TNFΔ69AU/+ mouse model, we show that low-grade inflammation accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Analysis of TAA cell heterogeneity further identifies a progenitor subpopulation enriched in the aged adipose tissue. Finally, heterochronic transplantation experiments suggest that the aged adipose tissue can serve as a systemic source of TAA cells and contribute to the conversion of young CD8+ T cells into the aged phenotype. Together, these findings indicate that aged non-lymphoid tissues actively drive CD8+ T cell remodeling and identify adipose tissue as an important niche shaping immune aging.
    Keywords:  CD8(+) T cells; CP: immunology; adipose tissue; aging; granzyme K; inflammaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117303
  13. Adv Sci (Weinh). 2026 Apr 21. e01083
    Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.
    Antoni Gañez-Zapater, Savvas Kourtis, Camilla Reiter Elbæk, Lorena Espinar, Carolina Toro-Márquez, Albert Coll-Manzano, Alfredo Smiriglia, Laura García-López, Laura Wiegand, Maria Guirola, Frédéric Fontaine, Andrea Morandi, André C Müller, Sara Sdelci.
      Progression through the cell cycle requires coordinated regulation of transcription, chromatin state, and cellular metabolism. While metabolic enzymes are known to localize the nucleus and influence chromatin states, how nuclear metabolism itself oscillates during the cell cycle remains unexplored. Here, we combine a customized FUCCI-3 reporter with chromatome mass spectrometry and high-throughput imaging to systematically resolve nuclear and chromatin-associated metabolic changes across cell cycle phases. We identify phosphatidylinositol metabolism as a nuclear pathway that oscillates with the cell cycle, with PIP5K1A, PLCD3, and PLD2 showing phase-specific nuclear and chromatin dynamics. Nuclear PIP2 levels redistribute within the nucleus depending on cell cycle stage. Downregulation of PIP5K1A reduces nuclear PIP2 levels, whereas nuclear enrichment of PIP5K1A increases PIP2 abundance in the nucleus and nucleolus, functionally linking PIP5K1A nuclear localization to nuclear PIP2 synthesis. Moreover, perturbation of nuclear PIP2 synthesis alters chromatin methylation, with a pronounced impact on H4K20 monomethylation. Together, our results reveal that nuclear phosphatidylinositol metabolism is cell cycle regulated and functionally linked to chromatin methylation, establishing nuclear lipid metabolism as a previously unrecognized layer of cell cycle control.
    Keywords:  cell cycle; chromatin; epigenetics; nuclear metabolism; proteomics
    DOI:  https://doi.org/10.1002/advs.202501083
  14. Ferroptosis Oxid Stress. 2026 ;pii: 202523. [Epub ahead of print]2(3):
    Ferroptosis surveillance: Insights from in vivo contexts.
    Alec J Vaughan, Mario Palma, Jessalyn M Ubellacker, Thales Papagiannakopoulos.
      Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.
    Keywords:  Ferroptosis; GPX4–FSP1 axis; in vivo modeling; microenvironment
    DOI:  https://doi.org/10.70401/fos.2026.0021
  15. FEBS Lett. 2026 Apr 19.
    Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
    Shiho Machii, Kazushi Morimoto, Pakawit Lerksaipheng, Mirinthorn Jutanom, Ken-Ichi Yamada.
      Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.
    Keywords:  PDH; PDK4; PPARα; cellular senescence; cystine deprivation; ferroptosis; mitochondrial function
    DOI:  https://doi.org/10.1002/1873-3468.70332
  16. Nat Metab. 2026 Apr 23.
    Measuring eating patterns in real life reveals high variability in timing and choices.
      
    DOI:  https://doi.org/10.1038/s42255-026-01503-1
  17. Cancer Discov. 2026 Apr 20. OF1-OF20
    LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
    Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L Wu, Mariana C S Mancini, Burcu Karadal-Ferrena, Sofia G Dimitriadoy, Michael Cross, Anna H Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-Lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E LeBoeuf, Ting Chen, Cynthia A Loomis, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J Tsay, Fernando Moreira Simabuco, Charles M Rudin, Andre L Moreira, Kamal M Khanna, Harvey I Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B Koralov, Thales Papagiannakopoulos.
      LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression.
    SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0470
  18. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00244-9. [Epub ahead of print]333 124220
    Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
    Yang Liu, Xu Zhou, Weilin Li, Bing Feng, Jingshan Sun, Ruzhen Li, Huixia Ma, Lanpeng Li, Feng Zhou, Jianxun Ding, Xuesi Chen.
      Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K+) as a metabolically coupled ionic immune checkpoint that suppresses CD8+ T cell antitumor immunity. Using a murine melanoma model with an elevated-K+ microenvironment, we demonstrate that excess extracellular K+ profoundly impairs CD8+ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K+-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K+-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K+-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8+ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.
    Keywords:  Adoptive cell therapy; Immunomodulatory biomaterials; Ionic immune checkpoint; K(+)-scavenging hydrogel; T cell metabolism
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124220
  19. J Clin Invest. 2026 Apr 23. pii: e194427. [Epub ahead of print]
    Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.
    Adam Majcher, Ranjha Khan, Kathrin Buder, Florence Bourquin, Julie D Saba, Thorsten Hornemann.
      Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) or nephrotic syndrome type 14 (NPHS14), is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency using patient fibroblasts, SGPL1-knockout HEK293T cells, and Sgpl1-/- and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labelling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (i) feedback regulation of de novo sphingolipid synthesis via the ORMDL-ceramide axis and (ii) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis - either by exogenous sphingolipid load or disruption of compensatory regulation - induces pathological intracellular S1P accumulation. In vivo, Sgpl1-/- mice exhibited pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho-ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with Fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho-ROCK hyperactivation as a tractable therapeutic target in SPLIS.
    Keywords:  Chronic kidney disease; Cytoskeleton; Genetics; Lipidomics; Metabolism; Nephrology
    DOI:  https://doi.org/10.1172/JCI194427
  20. FEBS J. 2026 Apr 24.
    Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
    Abdulsamie Hanano, Amal Yousfan.
      Fatty acids (FAs) are essential for cellular growth and homeostasis; however, their excessive accumulation induces lipotoxicity. To prevent FA-induced damage, eukaryotic cells sequester surplus FAs within cytosolic lipid droplets (LDs), dynamic organelles central to lipid storage, metabolism, and signaling. Emerging evidence indicates that LDs suppress ferroptosis, an iron-dependent programmed cell death, by channeling polyunsaturated fatty acids (PUFAs) away from membrane phospholipids, thereby limiting lipid peroxidation. Nonetheless, the molecular mechanisms linking LD biogenesis to ferroptosis susceptibility remain poorly defined. In a recent study published in The FEBS Journal, Kump et al., provided mechanistic insights into how triacylglycerol (TGs) biosynthesis and LD assembly regulate ferroptosis in cancer cells as a function of PUFA availability. Here, we discuss and contextualize their principal findings.
    Keywords:  Acyl‐CoA diacylglycerol acyltransferase; ferroptosis; lipid droplets; lipid peroxidation; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1111/febs.70567
  21. Aging Cell. 2026 May;25(5): e70496
    Fasting and Caloric Restriction Activate an ADIOL-NHR-91-Kynurenine Pathway Signaling Axis to Promote Healthspan.
    Ana Guijarro-Hernández, Shinja Yoo, George A Lemieux, Sena Komatsu, Abdullah Q Latiff, Rishika R Patil, Kaveh Ashrafi.
      The steroid hormone 5-androstene-3β,17β-diol (ADIOL) was discovered nearly a century ago in humans, yet its physiological functions have remained poorly understood. Using C. elegans, we identify ADIOL as essential for several pro-healthspan effects of fasting and caloric restriction (CR). These dietary restriction regimens activate an ADIOL-NHR-91-kynurenic acid signaling axis, partly through transcriptional programs associated with ADIOL biosynthesis. Within this axis, ADIOL acts through NHR-91, a C. elegans homolog of estrogen receptor β, to reduce levels of kynurenic acid, a neuromodulatory metabolite, thereby enhancing healthspan. Critically, ADIOL does not extend lifespan, indicating its healthspan benefits are independent of longevity, and even late-life supplementation is effective. Collectively, this work establishes ADIOL as a physiological link between metabolic cues and neural function, promoting health during aging via the kynurenine pathway. Given that in mammals ADIOL similarly is a ligand for estrogen receptor β and the kynurenine pathway influences neuroprotection mechanisms, ADIOL may represent an evolutionarily conserved signal by which dietary interventions enhance healthy aging.
    Keywords:  androstenediol; caloric restriction; estrogen receptor beta; fasting; healthy aging; kynurenic acid; learning; movement; steroids
    DOI:  https://doi.org/10.1111/acel.70496
  22. Nat Cancer. 2026 Apr 20.
    Heterogeneity and plasticity of cancer-associated fibroblasts.
    Sneha Pramod, Hagar Lavon, Ruth Scherz-Shouval, Mara H Sherman.
      Fibroblasts sense and respond to contextual cues to support tissue structure and function. In cancer, they engage a dysregulated wound-healing response that profoundly shapes tumor composition and progression. Efforts to therapeutically target these cancer-associated fibroblasts (CAFs) have been complicated by their heterogeneity and plasticity. However, recent advances, particularly in single-cell and spatial technologies, have greatly improved the understanding of the phenotypic consequences of distinct CAF states and functions. Here we review the current understanding of CAFs as heterogeneous, instructive regulators of tumor microenvironments across anatomic sites and highlight key challenges for the future.
    DOI:  https://doi.org/10.1038/s43018-026-01146-x
  23. Trends Cell Biol. 2026 Apr 18. pii: S0962-8924(26)00058-9. [Epub ahead of print]
    Senescent cell heterogeneity: origins, detection, and therapeutic implications.
    Rong Wu, Junyu Zhu, Hayoon Kim, Ming Xu.
      Although senescent cells are commonly characterized by stable cell cycle arrest, emerging evidence indicates that senescence is not a uniform state but a collection of highly heterogeneous phenotypes. This heterogeneity stems from biological factors, such as diverse senescence markers, cellular origins, and targeting mechanisms, as well as from technical variations in experimental approaches, notably in the design of transgenic mouse models. By summarizing recent advances in next-generation senolytic strategies, multiomics profiling, and genetically engineered mouse models of senescence, we provide an integrated perspective on the origins and consequences of senescent cell heterogeneity. Such a perspective is essential for refining investigative methodologies and for developing precise therapies that selectively target senescent cell populations whose roles have been experimentally validated in vivo.
    Keywords:  aging; p16; p21; senescence; senolytics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.015
  24. Cell Rep. 2026 Apr 17. pii: S2211-1247(26)00361-X. [Epub ahead of print]45(4): 117283
    Polyamine homeostasis in Caenorhabditis elegans relies primarily on transport.
    Cindy Chang, Ankur Jain.
      Polyamines are essential metabolites present in all cells, but their regulation in vivo remains poorly understood. Little is known about whether tissues maintain distinct polyamine setpoints, how these setpoints are established, or whether such differences underlie selective vulnerability in disease. Here, we applied single-cell polyamine measurements in living Caenorhabditis elegans to map tissue polyamine levels and their regulatory dependencies. Three principles emerge: (1) across differentiated tissues, steady-state polyamine pools are maintained primarily by transporter-mediated import rather than de novo synthesis. (2) The intestine functions as a systemic regulator: perturbing intestinal polyamines affects organism-wide levels, and intestine-specific rescue restores systemic balance. (3) Neurons maintain markedly low cytoplasmic polyamine pools and undergo subtype-specific developmental reprogramming, switching polyamine acquisition strategies as they mature. These findings define core principles of tissue-specific polyamine regulation in vivo and provide a framework for developing therapeutic strategies to restore polyamine balance.
    Keywords:  C. elegans; CP: Metabolism; Polyamines; metabolism; tissue-specific regulation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117283
  25. Aging Cell. 2026 May;25(5): e70510
    Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
    Mary P Udumula, Anjaly Km, Faraz Rashid, Mohammad Nematullah, Harshit Singh, Tanya Bhardwaj, Miriana Hijaz, Shailendra Giri, Eduardo N Chini, Heather M Gibson, Ramandeep Rattan.
      Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4+ and CD8+ T cell responses and a marked expansion of FOXP3+ Tregs exhibiting elevated IL-10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α-ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate-driven metabolic reprogramming as a central mechanism of age-related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.
    Keywords:  Tregs; aging; immunosuppression
    DOI:  https://doi.org/10.1111/acel.70510
  26. Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166
    Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
    Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.
      Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.
    Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes
    DOI:  https://doi.org/10.1016/j.redox.2026.104166
  27. FEBS J. 2026 Apr 24.
    Fast & fuelious: the malate-aspartate shuttle in brown adipocyte lipid metabolism.
    Lukas Blaas, Alexander Bartelt.
      Brown adipose tissue (BAT) produces heat in response to cold exposure, for which it relies on the coordination of aerobic and anaerobic metabolism. However, how reaction intermediates connect these two essential pathways is unclear. In this issue of The FEBS Journal, Veliova et al., report that the malate-aspartate shuttle (MAS) supports norepinephrine-induced lipolysis in brown adipocytes. Disruption of MAS during adrenergic activation impairs lipolysis without reducing respiration. These findings indicate that cytosolic redox balance influences thermogenic metabolism. By linking NAD+ regeneration to lipid metabolism, the study highlights the MAS as an important node coordinating metabolism, redox balance, and thermogenesis.
    Keywords:  brown adipose tissue; lipid mobilization; malate–aspartate shuttle; metabolic redox balance; thermogenesis
    DOI:  https://doi.org/10.1111/febs.70557
  28. Cell Metab. 2026 Apr 22. pii: S1550-4131(26)00148-8. [Epub ahead of print]
    Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
    Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.010
  29. Cell Metab. 2026 Apr 22. pii: S1550-4131(26)00111-7. [Epub ahead of print]
    Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
    Anthony H Tsang, Nicholas Heeley, Constanza Alcaino, Eunsang Hwang, Brian Y Lam, Taufiq Rahman, Tamana Darwish, Danae Nuzzaci, Richard G Kay, Amar Sarkar, Ruiyan Wang, Nihal Basha, Austin Punnoose, Peter Kirwan, Marcella Ma, Giles S Yeo, Florian T Merkle, Fiona M Gribble, Frank Reinmann, Kevin W Williams, Clémence Blouet.
      Dietary protein promotes satiety and weight loss, yet how appetite-regulating neurons sense dietary protein remains poorly understood. Here, we show that Cacna1g, which encodes the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates neuronal leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of pro-opiomelanocortin (POMC) neurons in cultured neurons and brain slices, thereby suppressing the anorectic response to hypothalamic leucine in vivo. Genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, leucine binds a hydrophobic pocket of Cav3.1 and lowers its threshold for voltage-dependent activation. Finally, pharmacological activation of mediobasal hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates responses to anorectic agents, including liraglutide. Together, these findings establish hypothalamic Cav3.1 as a neuronal leucine sensor and nominate it as a tractable target for anti-obesity therapy.
    Keywords:  POMC neurons; appetite; arcuate nucleus; dietary proteins; hypothalamus; leucine; metabolic diseases; nutrient sensing; obesity; voltage-gated calcium channel
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.017
  30. Nature. 2026 Apr 22.
    Glycerol-driven TNAP activation in thermogenesis and mineralization.
    Mohammed Faiz Hussain, Shreya S Krishnan, Brittany L Carroll, Bozena Samborska, Aisha Mousa, Alice Williamson, Maria Delgado-Martin, Bindu Y Srinivasu, Jakub Bunk, Janane F Rahbani, Abel Oppong, Anna Roesler, Zafir Kaiser, Mina Ersin, Qiaoqiao Zhang, Maria Guerra Martinez, Abhirup Shaw, Jonathan Cheng, Hannah Klemets, Katalin Kocsis Illes, Victoria E DeMambro, Clifford J Rosen, José Luis Millán, Thomas E Wales, Claudia Langenberg, Marc D McKee, Alba Guarné, Lawrence Kazak.
      Tissue-nonspecific alkaline phosphatase (TNAP) promotes skeletal mineralization by hydrolysing pyrophosphate1 and has been linked to uncoupling protein 1 (UCP1)-independent adipocyte thermogenesis through the futile creatine cycle through phosphocreatine hydrolysis2,3. Despite TNAP's broad physiological roles, endogenous regulators of its activity have not been defined. Furthermore, the activation mechanism of UCP1-independent thermogenesis has remained unresolved. Here we identify glycerol as an allosteric activator of TNAP. Glycerol binds to a surface pocket distal to the active site, which we term the glycerol pocket, to enhance TNAP activity. Using biophysical, structural, bioenergetic and physiological approaches, we show that the glycerol pocket is required for TNAP-driven thermogenesis. Through this mechanism, TNAP activates the futile creatine cycle, acting as a physiological complement to UCP1. The glycerol pocket is likewise required for optimal osteoblast-regulated mineralization. Human missense variants in this site reduce TNAP-dependent mineralization in vitro and are associated with lower alkaline phosphatase activity and bone mineral density, providing genetic evidence that its disruption impairs skeletal physiology.
    DOI:  https://doi.org/10.1038/s41586-026-10396-9
  31. Trends Immunol. 2026 Apr 18. pii: S1471-4906(26)00070-0. [Epub ahead of print]
    Local cues, local killers: human natural killer cells across tissues.
    Annika Niehrs, Kejsi Zeqiraj, Andrea Ponzetta, Niklas K Björkström.
      Natural killer (NK) cells are part of the innate immune system and reside in multiple tissues. During steady-state conditions, they contribute to tissue homeostasis, while in disease settings, tissue-resident (tr) NK cells are positioned at the frontline of immune surveillance. Due to their exposure to local microenvironments, NK cells residing outside the bloodstream exhibit phenotypic, transcriptional, functional, and metabolic features that distinguish them from their circulating counterparts. In this review, we outline the defining characteristics of tr NK cells, discuss their recirculation potential, and summarize their functional and metabolic specialization across human tissues. Finally, using cancer as an example, we highlight how tr NK cells are altered in disease and how local tissue environments shape their functional states.
    Keywords:  immunometabolism; tissue microenvironment; tissue-resident NK cells
    DOI:  https://doi.org/10.1016/j.it.2026.03.009
  32. Nature. 2026 Apr 22.
    Early fibrotic niches establish tumour-permissive microenvironments.
    Erik C Cardoso, Hyeyoung Lee, Frances J England, Hyunjin Cho, Robin Lu, Sagar S Varankar, Moo Suk Park, Natasha Rekhtman, Bon-Kyoung Koo, Benjamin D Simons, Jinwook Choi, Joo-Hyeon Lee.
      Pathologic transformation represents a critical yet poorly defined window during which mutant epithelial stem cells actively construct the microenvironment that enables tumour initiation1,2. Here using integrated single-cell, spatial and functional analyses, we define the earliest multicellular events that licence this transition following oncogenic activation in the lung. KrasG12D-mutant alveolar type II cells rapidly adopt regenerative-like states that act as signalling hubs, orchestrating coordinated stromal and immune reprogramming while enhancing epithelial plasticity. Through secretion of amphiregulin, mutant epithelial cells activate EGFR signalling in adjacent fibroblasts, inducing a fibrotic, injury-like programme. Reprogrammed fibroblasts, in turn, expand and reprogramme alveolar macrophages, amplifying inflammatory signalling and reinforcing epithelial plasticity. These reciprocal interactions establish a self-sustaining epithelial-stromal-immune circuit that generates a tumour-permissive niche before malignant outgrowth. Disruption of the amphiregulin-EGFR axis prevents early niche formation and abrogates tumour initiation. Conservation of this programme in KRASG12D-inducible human alveolar organoids and early-stage lung adenocarcinoma tissues identifies epithelial-microenvironment communication as a therapeutically actionable vulnerability and suggests that intercepting niche formation may prevent progression to treatment-resistant disease.
    DOI:  https://doi.org/10.1038/s41586-026-10399-6
  33. Trends Endocrinol Metab. 2026 Apr 22. pii: S1043-2760(26)00045-7. [Epub ahead of print]
    Energy constraint on human health.
    Alexander Behnke, Evan Shaulson, Herman Pontzer, Christopher P Kempes, Martin Picard.
      Evolved constraints to human energy transformation force the body-brain system to operate an economy of energy. To survive and thrive, an organism's finite internal energy resources must be dynamically reallocated, forcing trade-offs from organelle to organism. Building on an energy trade-off framework integrating life history theory and cellular biology, we propose that energy trade-offs occur between three main classes of processes relevant to health: (i) vital, (ii) stress, and (iii) growth, maintenance, and repair (GMR). Competing demands for these processes exist within a hierarchy of energy needs where more 'urgent' vital- and stress-related functions are prioritized by suppressing longevity-promoting growth, maintenance, and repair processes. The energy constraint model of human health provides an energy-based framework to address health/disease dynamics across the lifespan.
    Keywords:  aging; bioenergetics; disease; energy compensation; evolution; exercise; healing; metabolic compensation; mind-body; mitochondria; stress; trade-offs
    DOI:  https://doi.org/10.1016/j.tem.2026.02.010
  34. Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770
    A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
    Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.
      Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.
    Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
  35. EMBO J. 2026 Apr 22.
    Structure-guided optimization of SLC1A1/EAAT3-selective inhibitors targeting renal cancer metabolism.
    Pooneh Koochaki, Biao Qiu, Jesse A Coker, Alexander Earsley, Nancy S Wang, Todd Romigh, Christopher M Goins, Carleigh Salem, Dehui Mi, Emily Days, Joshua A Bauer, Shaun R Stauffer, Olga Boudker, Abhishek A Chakraborty.
      Renal cell carcinomas (RCCs) depend on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. Here we determined a cryo-EM structure of human SLC1A1 bound to compound 3e, a recently described SLC1A1-selective bicyclic imidazo[1,2 α]pyridine-3-amine (BIA) inhibitor with an unclear mechanism of action. 3e binds a membrane-embedded allosteric pocket accessible only in the apo state, when SLC1A1 is unbound to substrate and sodium, and likely prevents sodium and substrate binding. Moreover, by forming a wedge between the trimerization domain and the substrate-binding transport domain, alongside a cholesterol moiety from the lipid bilayer, 3e blocks SLC1A1's elevator-like movements that support the transport cycle. Mutations in this binding pocket abolish the 3e interaction and counteract 3e's cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. The subsequent design of two new SLC1A1-selective BIA derivatives, PBJ1 and PBJ2, was directed by the SLC1A1-3e structures; both inhibited SLC1A1-dependent aspartate, glutamate, and cysteine metabolism and showed enhanced cytotoxicity.
    DOI:  https://doi.org/10.1038/s44318-026-00776-2
  36. JHEP Rep. 2026 Apr 17. pii: S2589-5559(26)00129-1. [Epub ahead of print] 101858
    Targeting RuvBL1 disrupts mitochondrial metabolism and structure in hepatocellular carcinoma.
    Tommaso Mello, Irene Simeone, Alice Guida, Dimitri Papini, Francesca Begnozzi, Alice Santi, Daniele Guasti, Patrizia Nardini, Simone Polvani, Matteo Lulli, Oxana Bereshchenko, Elisabetta Ceni, Armando Curto, Paolo Pinton, Massimo Bonora, Andrea Galli.
       BACKGROUND & AIMS: The AAA+ ATPase RuvBL1 takes part in several biological processes, including chromatin remodelling and DNA repair, ribosome biogenesis, mTOR signalling, and oncogenic transformation. RUVBL1 overexpression correlates with poor survival in hepatocellular carcinoma patients. We previously found that RuvBL1 is a key regulator of liver glucose metabolism in mice. Here, we aimed at disentangling the metabolic function of RuvBL1 in HCC cells.
    METHODS: Non-transformed AML-12, primary mouse hepatocytes, HCC cell lines, and RuvBL1hep-/- mice were used (n=3). RuvBL1 was targeted by RNAi and by inhibition with CB-6644. Metabolomic profiling and mitochondrial functions were assessed by targeted GC/MS, Seahorse analysis, and ATP synthase activity. Mitochondrial morphology and membrane potential were investigated by fluorescence microscopy, High-Content Imaging, and TEM. Mitochondrial RuvBL1 was detected by WB, super-resolution microscopy, TEM, and PLA. Human HCC and normal liver samples from TCGA and GTEx databases were used for in silico analysis (T=369, N=160).
    RESULTS: Targeting RuvBL1 impairs mitochondria-centred metabolic processes, including amino acid metabolism, TCA cycle, and OXPHOS. Inhibition of RuvBL1/2 activity induces loss of cristae integrity, mitochondrial hyperpolarization and fragmentation, a phenotype paralleled by the hepatocytes of RuvBL1hep-/- mice. We detected RuvBL1 in proximity to mitochondrial ATP synthase, a previously unreported localization for this protein. Mechanistically, CB-6644 reduces ATP synthase-RuvBL1 interaction and impairs complex V activity even under a fuelled TCA cycle. In human HCC, higher RUVBL1 expression correlates with gene signatures associated with mitochondrial oxidative phosphorylation (FDR=5.64e-03), ATP synthase complex (FDR=6.03e-03), and poorer outcome (p=2e-07).
    CONCLUSIONS: Targeting RuvBL1 impairs complex V activity, disrupting mitochondrial metabolic functions and structural integrity. The mitochondrial functions of RuvBL1 may inform novel therapeutic strategies in the fight against hepatocellular carcinoma.
    IMPACT AND IMPLICATIONS: Metabolic reprogramming is a key feature driving HCC onset, progression, and plasticity, contributing to treatment resistance and poor prognosis. RUVBL1 overexpression correlates with reduced survival of HCC patients and has emerged as a potential metabolic modulator. In this study, we found that targeting RuvBL1 impairs its interaction with mitochondrial ATP synthase, disrupting mitochondrial metabolism and cristae structure. In human HCC samples, RUVBL1 expression correlates with hallmark mitochondrial metabolic processes. These findings may inform the development of targeted therapeutic approaches aimed at impairing the metabolic rewiring and plasticity of HCC.
    Keywords:  ATP synthase; OXPHOS; TCA cycle; amino acids metabolism; ketogenesis; liver cancer; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.jhepr.2026.101858
  37. Nat Commun. 2026 Apr 20.
    SPNS2 exports sphingosine-1-phosphate and imports glucose.
    Cynthia Weigel, Md Lokman Hossen, Ryan D R Brown, Can E Senkal, Christopher D Green, Jason Newton, Sumit Saha, Elisa N D Palladino, Bin Ni, Francesco S Celi, Xianjun Fang, Frank D Corwin, Huanyu Z Li, David B Sauer, Prem P Chapagain, Sarah Spiegel.
      Spinster homolog 2 (SPNS2) exports the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) out of cells to regulate processes important for health and diseases. However, the molecular mechanism underlying SPNS2 transport functions and its precise physiological roles are not fully understood. Here, through a series of complementary approaches in mice, cellular assays, and particularly with in vitro cell-free binding and transport assays, we show that SPNS2 has antiporter-like activity, transporting S1P out of cells and glucose in. We demonstrate that SPNS2 directly binds glucose and transports it and identify key amino acid residues of SPNS2 involved in glucose engagement and import. Our data reveal that S1P, which enters from the cytosolic side of SPNS2 facilitates conformational changes, enabling extracellular glucose to move inward through the central cavity. Thus, we identify a mechanism that dynamically contributes to glucose homeostasis in response to metabolic and sphingolipid cues with clinical and pathophysiological implications.
    DOI:  https://doi.org/10.1038/s41467-026-71659-7
  38. Nat Rev Mol Cell Biol. 2026 Apr 21.
    The regulation, function and disease relevance of cytoplasmic tRNAs.
    Robin E Stanley, Todd M Lowe, Zoya Ignatova.
      Transfer RNAs (tRNAs) are core components of protein synthesis. Recent studies and technological advances have expanded our understanding of the complexities of tRNA biology. In this Review, we discuss the genomic organization and spatiotemporal expression of human cytoplasmic tRNAs, the quality control pathways that govern their maturation and functionality, and how dysregulation of tRNA biogenesis and function contributes to human pathologies. We also present emerging concepts regarding how tissue-specific tRNA abundance regulates translation velocity and how tRNAs are centrally involved in surveillance and stress signalling pathways, including ribosome-associated quality control and the integrated stress response. We further discuss the potential of tRNA-based therapeutics, highlighting new strategies to address tRNA-associated translation defects. By bridging between molecular tRNA biology and its clinical implications, we emphasize the crucial need to understand the intricacies of tRNA regulation in order to therapeutically target them in a variety of diseases.
    DOI:  https://doi.org/10.1038/s41580-026-00963-3
  39. Cell. 2026 Apr 17. pii: S0092-8674(26)00344-2. [Epub ahead of print]
    2'3'-cGAMP-induced membrane shearing promotes broad antiphage immunity.
    Yina Gao, Zhaolong Li, Yufei Zhou, Weimin Li, Quanjin Li, Jingge Wang, Miao Shi, Feng Ye, Chunqiu Zhao, Songqing Liu, Qiuyao Jiang, Yun Zhu, Fei Sun, Ang Gao, Pu Gao.
      Cyclic-oligonucleotide-based anti-phage signaling system (CBASS), a central prokaryotic antiviral strategy and evolutionary ancestor of the mammalian cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, relies on cyclic-nucleotide-activated effectors to elicit immunity. The most prevalent effectors are transmembrane (TM) proteins, yet their mechanisms remain unknown. Here, we show how a representative three transmembrane (3TM)-SMODS-associated fused to various effector domains (SAVED) effector couples ligand sensing to membrane disruption. Upon binding 2'3'-cyclic GMP-AMP (cGAMP)-synthesized by bacterial cGAS/DncV-like nucleotidyltransferase (CD-NTase) with features resembling mammalian cGAS-3TM-SAVED assembles stepwise from an apo monomer through a transient dimer into extended filaments. Filament assembly employs 2'3'-cGAMP as molecular glue linking SAVED domains and reorients TM helices and amphipathic hairpins into vertically offset arrays. Both arrays bear opposing hydrophobic and hydrophilic faces, thereby driving vertical lipid shearing. This shearing generates a linear pore array that permeabilizes membranes and triggers cell death. These findings uncover the long-missing mechanism of CBASS TM effectors and establish vertical membrane shearing as an unrecognized principle of membrane disruption across domains of life.
    Keywords:  CBASS; CD-NTase; SAVED; antiphage; cGAMP; cGAS; cell death; membrane disruption; membrane shearing
    DOI:  https://doi.org/10.1016/j.cell.2026.03.043
  40. Curr Opin Cell Biol. 2026 Apr 17. pii: S0955-0674(26)00031-1. [Epub ahead of print]100 102643
    Cancer signaling beyond the genes.
    Andre Levchenko, Ralitsa R Madsen.
      Cancer is still largely interpreted through the lens of genetic mutations, which continues to shape most therapeutic strategies. Yet single cell analyses reveal limits to this view: phenotypic heterogeneity is pervasive even among genetically identical cancer cells, and many canonical driver mutations are also present in non-malignant tissues. These paradoxes can be reconciled by viewing cancer as a new tissue state characterized by aberrant cellular information processing, where mutations act as context-dependent modifiers of the signaling codes. We advance a framework in which input-specific signaling dynamics determine phenotypic outcomes, while oncogenic mutations bias and blur these dynamics rather than acting as simple "on-off" switches. In this view, therapeutic success depends on restoring the fidelity of dynamic signal encoding and decoding rather than merely inhibiting isolated pathway components.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102643
  41. Cell Metab. 2026 Apr 21. pii: S1550-4131(26)00108-7. [Epub ahead of print]
    A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
    Jiawei Chen, Ya Ren, Yong Zhou, Ziyang Wang, Kehang Mao, Zhengqing Yu, Jiyang Li, Xiaoxiao Guo, Hao Xu, Yiyang Wang, Yi Wang, Bo Pang, Hongxiao Liu, Huiru Tang, Jing-Dong J Han.
      Understanding aging and complex diseases requires diverse data, ranging from molecular profiles to imaging and routine clinical tests. However, most multi-omic datasets measure only a subset of modalities and are confounded by batch effects. Here, we present AURORA (AI unification and reconstruction of omics reassembly atlas), a generative deep-learning platform that integrates seven modalities (including transcriptomics, metabolomics, microbiome, 3D and thermal facial imaging, and clinical laboratory tests) across 581,763 samples from 425,258 individuals. AURORA harmonizes batch effects and reconstructs missing data across modalities, enabling highly accurate multimodal aging clocks and disease risk predictors. It also supports personalized in silico perturbation analyses to predict intervention and drug responses, validated using longitudinal cohorts. As a proof of concept, we provide a prototype AI agent that converts single-input modalities into a multimodal report for users and researchers. Together, AURORA links non-invasive inputs to comprehensive aging biomarkers and therapeutic discovery.
    Keywords:  aging clocks; biological aging; digital twin; disease risk prediction; drug repurposing; facial imaging; generative AI; in silico perturbation; multi-omics integration; personalized medicine
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.014
  42. PLoS Pathog. 2026 Apr;22(4): e1014056
    Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.
    Stefano Sellitto, Davide Caredio, Matteo Bimbati, Giovanni Mariutti, Martina Cerisoli, Lukas Frick, Vangelis Bouris, Carlos Omar Oueslati Morales, Dalila Laura Vena, Sandesh Neupane, Federico Baroni, Kathi Ging, Jiang-An Yin, Elena De Cecco, Andrea Armani, Adriano Aguzzi.
      Heterogeneous Nuclear Ribonucleoprotein K (hnRNP K) is a limiting factor for prion propagation. However, little is known about the function of hnRNP K except that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2γ (TFAP2C) suppressed the death of hnRNP K-depleted LN-229 and U-251 MG cells, whereas its overexpression hypersensitized cells to hnRNP K loss. HNRNPK ablation decreased cellular ATP, downregulated genes related to lipid and glucose metabolism, and enhanced autophagy. Co-occurrent deletion of TFAP2C reversed these effects, restoring transcriptional balance and alleviating energy deficiency. We linked HNRNPK and TFAP2C functional and genetic interaction to mTOR signaling, observing that hnRNP K depletion inhibited mTORC1 activity through downregulation of mTOR and Rptor, while TFAP2C overexpression enhanced mTORC1 downstream functions. In prion-infected cells, TFAP2C activation reduced prion levels and countered the increased prion propagation caused by HNRNPK suppression. Short-term inhibition of mTORC1 also elevated prion levels and partially mimicked the effects of HNRNPK silencing. Our study identifies TFAP2C as a genetic interactor of HNRNPK, implicates their roles in mTOR metabolic regulation, and establishes a causative link between these activities and prion propagation.
    DOI:  https://doi.org/10.1371/journal.ppat.1014056
  43. bioRxiv. 2026 Apr 03. pii: 2026.03.31.715667. [Epub ahead of print]
    Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice.
    Bailey A Knopf, Isaac Grunow, Brady Anderson, Tareq Rihawi, Michelle M Sonsalla, Mariah F Calubag, Reji Babygirija, Yang Liu, Fan Xiao, Chung-Yang Yeh, Dudley W Lamming.
      Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.
    DOI:  https://doi.org/10.64898/2026.03.31.715667
  44. Nat Commun. 2026 Apr 20. pii: 3410. [Epub ahead of print]17(1):
    Disruption of the SAGA CORE triggers collateral degradation of KAT2A.
    Paul Batty, Hannah Beneder, Caroline Schätz, Gabriel Onea, Maciej Zaczek, Ana P Kutschat, Miriam Abele, Sophie Müller, Giulio Superti-Furga, Georg E Winter, Davide Seruggia.
      The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex regulates gene expression through histone acetylation at promoters, mediated by its histone acetyl transferase (HAT), KAT2A. While SAGA structure and function are well characterised, mechanisms controlling the stability of individual subunits, including KAT2A, remain unclear. Here, using a fluorescence-based KAT2A stability reporter, we systematically dissect the molecular dependencies controlling KAT2A protein abundance, and identify the non-enzymatic SAGA CORE module subunits-TADA1, TAF5L, and TAF6L- as necessary for KAT2A stability. Loss of these subunits disrupts SAGA complex integrity, leading to non-chromatin-bound KAT2A that is degraded by the proteasome and consequent reduced H3K9 acetylation. Proteomic profiling reveals progressive loss of components from the CORE and HAT modules upon acute SAGA CORE disruption, indicating that an intact CORE is required for the stability of numerous SAGA components. Finally, a focused CRISPR screen of ubiquitin-proteasome system genes identifies the E3 ligase UBR5, a known regulator of orphan protein degradation, and the deubiquitinase OTUD5, as regulators of KAT2A degradation when the SAGA CORE is perturbed. Together, these findings reveal a dependency of KAT2A protein stability on SAGA CORE integrity and define an orphan quality control mechanism targeting unassembled KAT2A, revealing a potential vulnerability in SAGA-driven malignancies.
    DOI:  https://doi.org/10.1038/s41467-026-71613-7
  45. Sci Signal. 2026 Apr 21. 19(934): eadu5769
    mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
    Keita Uchida, Emily A Scarborough, Elizabeth Pruzinsky, Kathlyene R Stone, Hali Hartman, Daniel P Kelly, Jonathan J Edwards, Izhak Kehat, Benjamin L Prosser.
      Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK-dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK-dependent phosphorylation of 4EBP1 at Ser64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.
    DOI:  https://doi.org/10.1126/scisignal.adu5769
  46. Nature. 2026 Apr 22.
    Focal white matter lesions drive grey matter inflammation and synapse loss.
    Omar de Faria, Stavros Vagionitis, Andrea Lopez-Lopez, Michael Perry, Joseph Jo Yin Wong, Leslie Rodríguez-Kirby, Bastien Hervé, Balazs Viktor Varga, Eneritz Agirre, Sabrina Ghosh, Sebastian Timmler, Mert Yucel, Andrew T Setley, Kimberley Anne Evans, Tanja Mist Birgisdóttir, Sindri Gíslason, Yan Ting Ng, Courtney Kremler, Helene O B Gautier, Yasmine Kamen, Helena Pivonkova, Katrin Volbracht, Felix Hildebrand, Christian A Cepeda, Javier Rueda-Carrasco, Soyon Hong, George Malliaras, Sabine Dietmann, Gonçalo Castelo-Branco, Ragnhildur Thóra Káradóttir.
      Focal white matter lesions occur in most neurodegenerative disorders1-3. Despite occurring early in disease, white matter lesions are considered to be independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity4-7. Notably, their functional effect on neuronal circuits remains understudied. To address this, we generated a focal white matter lesion in the rat brain within a clinically relevant, anatomically well-defined circuit, in which these lesions occur in many neurodegenerative disorders8-10. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglial engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered to be detrimental; however, we show that it is an integral part of regeneration and is conserved across three distinct mouse circuits and lesioning methods. Preventing these transient changes in the grey matter blocks myelin regeneration in the white matter. Conversely, inducing myelin regeneration failure leads to chronic grey matter neuroinflammation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration7,11,12. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function, which may underlie multiple neurodegenerative conditions, and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.
    DOI:  https://doi.org/10.1038/s41586-026-10414-w
  47. Nat Commun. 2026 Apr 20.
    Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking.
    Justin A Bosch, Pierre Michel Jean Beltran, Cooper Cavers, James Thai LaGraff, Randy Melanson, Ankita Singh, Weihang Chen, Yanhui Hu, Sudhir Gopal Tattikota, Ying Liu, Yousuf Hashmi, John M Asara, Tess Branon, Alice Y Ting, Steven A Carr, Norbert Perrimon.
      Secreted proteins regulate many aspects of animal biology and are attractive targets for biomarkers and therapeutics. However, comprehensively identifying the "secretome", along with their tissues of origin, remains extremely challenging. To address this, we employed multiple 'omics methods to define a tissue-secretome map of 535 blood plasma proteins derived from specific cell-types and organs in Drosophila melanogaster. This map was enabled by methodological improvements including a collection of transgenic flies to label endogenous secreted proteins in 10 major tissue types, large-scale blood isolation, whole animal snRNA-seq, and 40 CRISPR knock-in strains. Using this map, we identify features of circulating proteins: most originate from specific tissues including unusual sources (e.g. glia), many are uncharacterized, and some are shed ectodomains of transmembrane proteins. In addition, in vivo experiments revealed circulating proteins with tissue-specific expression, as well as proteins that are deposited in a different tissue from where they are synthesized, suggesting potential inter-organ functions. Our secretome map will serve as a resource to investigate blood protein function, discover candidate tissue-tissue communication signals, and mine for homologues of human biomarkers.
    DOI:  https://doi.org/10.1038/s41467-026-71763-8
  48. Nature. 2026 Apr 22.
    Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
    JRI Live Cell Bank
      Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41586-026-10343-8
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