bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–05–24
sixty papers selected by
Christian Frezza, Universität zu Köln
  1. Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
  2. Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
  3. Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
  4. "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
  5. Intracellular potassium levels orchestrate circadian rhythmicity and cell division.
  6. Branching out takes anti-tumor immunity down a NOTCH.
  7. Cystine C-S bond cleavage fuels cysteine production under disulfide reductase deficiency.
  8. Shaping Human Health and Nutrition Through Innovations in Spatial Metabolism.
  9. Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
  10. Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
  11. Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress.
  12. Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
  13. Acetyl-CoA Synthetase 1 regulates global histone propionylation and metabolic stress responses.
  14. Rhythmic Nuclear Import Mediated by Importins Regulates the Neurospora Circadian Clock.
  15. Endothelial Drp1 integrates VEGF-induced redox signaling with glycolysis through cysteine oxidation to drive angiogenesis.
  16. SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
  17. Autophagy modulation in cancer.
  18. Stress granules shape ferroptosis in cancer.
  19. Tools and Technologies for Studying Cancer Metabolism.
  20. Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.
  21. Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.
  22. Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.
  23. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  24. G0 or no-G0: phosphatase control of quiescence and cell cycle entry.
  25. Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk.
  26. CPT1A loss promotes lung metastasis in immune-competent mice via a mechanism of mtDNA release and chronic activation of STING pathway.
  27. GPX4 regulates lipid peroxidation and ferroptosis of stored red blood cells.
  28. Atomic elementary flux modes explain the steady state flow of metabolites in large-scale flux networks.
  29. NRF2 Coordinates Ferroptosis and Disulfidptosis in Dermal Papilla Cells via Redox Metabolic Reprogramming in Androgenetic Alopecia.
  30. Mapping where mouse models match - and miss - human tumor immunity.
  31. In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging.
  32. Biophysical principles of cell competition and elimination.
  33. Mpi-driven N-glycosylation orchestrates mucin O-glycosylation and intestinal homeostasis.
  34. Glycerol is a new ally for heat production and bone health.
  35. Too little or too much sleep is linked to faster ageing throughout the body.
  36. Genome instability triggers intercellular DNA transfer between human cells.
  37. Metabolic robustness is an emergent property of hierarchical network organization in yeast.
  38. Rethinking the origins and functions of adaptive immunity.
  39. ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis.
  40. High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities.
  41. PBRM1-VHL cooperation rewires lipid and iron metabolism to promote ferroptosis resistance in clear cell renal cell carcinoma.
  42. From whole-body to organ-specific biological age clocks.
  43. β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.
  44. Localized heme sensing through a ternary molecular glue.
  45. Autoinhibitory feedback preserves intestinal stem cell maintenance and fate commitment.
  46. A multimodal adaptive optical microscope for in vivo imaging from molecules to organisms.
  47. Metabolic vulnerabilities in pleural mesothelioma.
  48. Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.
  49. Glucuronidation metabolomic fingerprinting to map host-microbe metabolism.
  50. MIF mediates monocyte-dependent inhibition of natural killer cell cytotoxicity in triple-negative breast cancer.
  51. Metabolic Coherence of the Mouse Brain.
  52. Lipopolysaccharide stimulates dynamic changes in B cell metabolism to promote proliferation.
  53. Multinucleation as a recurring evolutionary strategy for scaling and plasticity.
  54. Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.
  55. Beyond Kleiber's Law: Variation and Mechanisms of Metabolic Scaling.
  56. H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.
  57. Nrf2 modulates cytosolic and mitochondrial calcium signal.
  58. Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation.
  59. Skin aging: mechanisms, evaluation, and rejuvenation.
  60. Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
  1. Nat Aging. 2026 May;6(5): 987-1006
    Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
    Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.
      Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.
    DOI:  https://doi.org/10.1038/s43587-026-01122-1
  2. Nature. 2026 May 20.
    Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
    Ram P Chakrabarty, Jonathan G Van Vranken, Yuki Aoi, Taylor A Poor, Gregory S McElroy, Karthik Vasan, Shimaa H A Soliman, Marta Iwanaszko, Rogan A Grant, Benjamin C Howard, Colleen R Reczek, Anjali D Chandel, Michael Kahl, Zhaofa Xu, Kathryn A Helmin, Qiushi Jin, Dongmei Wang, Peng Gao, Jenna L E Blum, Zachary L Sebo, Feng Yue, Yongchao C Ma, Shawn M Davidson, Steven P Gygi, Samuel E Weinberg, Benjamin D Singer, SeungHye Han, Ali Shilatifard, Navdeep S Chandel.
      L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.
    DOI:  https://doi.org/10.1038/s41586-026-10564-x
  3. Nat Metab. 2026 May 18.
    Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
    Annamaria Regina, Francesca Solagna, Malkon Sanchez Estrada, Maaike M E Jacobs, Daniel Martinez-Martinez, Theodoros Georgomanolis, Irma Alibashikj, Sara Gjurgji, Claire Pearson, Dehui Chang, Chrysanthi Moschandrea, Ana Sagrera Aparisi, Elena Crespo, Jessica Buechel, Farina Schneider, Lea Trojahn, Paulina Pfelzer, Milica Popovic, Elena Potenza, Agnieszka M Kabat, Carien Niessen, Borko Amulic, Niloufar Safinia, Sara Cogliati, David E Sanin, Matteo Villa, Edward J Pearce, Christian Frezza, Erika L Pearce, Filipe Cabreiro, Fiona Powrie, Mauro Corrado.
      Loss of host-microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (Treg) cells to preserve gut-immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired Treg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs Treg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut-immune homeostasis and dictates outcome in pathobiont infections.
    DOI:  https://doi.org/10.1038/s42255-026-01533-9
  4. Cell Chem Biol. 2026 May 21. pii: S2451-9456(26)00147-9. [Epub ahead of print]33(5): 591-593
    "SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
    Qing Zhang, Trina Chia Min Tan, Vincenzo Sorrentino.
      Nicotinamide adenine dinucleotide (NAD+) is a metabolic redox cofactor whose compartmentalization in mitochondria is crucial for cellular function; however, its regulation mechanisms are largely unknown. In a recent Cell publication, Jia et al.1 uncover that the enzyme SelO catalyzes mitochondrial NAD+ hydrolysis to regulate β-oxidation and maintain mitochondrial and liver homeostasis.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.04.012
  5. Nat Commun. 2026 May 22.
    Intracellular potassium levels orchestrate circadian rhythmicity and cell division.
    Sergio Gil Rodríguez, Louise L Hansen, Olivia J P Fraser, Yen Peng Chew, Rebecca K Spangler, Ellen Grünewald, Andrew D Beale, Beverley M Rabbitts, Alessandra Stangherlin, John S O'Neill, Carrie L Partch, Priya Crosby, Gerben van Ooijen.
      Circadian (~24 h) rhythms are a fundamental feature of life, and their disruption increases the risk of infectious diseases, metabolic disorders, and cancer. We previously identified circadian oscillations in intracellular potassium concentrations in cells across kingdoms. Using highly divergent eukaryotic cell types, we now show that potassium levels act to regulate the period and phase of clock gene expression rhythms, therefore establishing intracellular potassium as a bona fide regulator of cellular circadian rhythms. Intracellular potassium also regulates critical events in the cell cycle. Strikingly, we observe that manipulating potassium levels inhibits cell proliferation in a circadian phase-dependent manner. As the timing of cell division is tuned by the circadian clock, we hypothesised that potassium rhythms could mechanistically link cell proliferation rhythms to the circadian cycle. In line with this hypothesis, we find that potassium levels are not only sufficient to instruct the timing of cell proliferation, but also essential to maintain coherent coupling between circadian rhythms and proliferation rhythms. These results establish circadian potassium rhythms as a primary factor coupling the cell- and circadian cycles in eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41467-026-73351-2
  6. Nat Immunol. 2026 May 22.
    Branching out takes anti-tumor immunity down a NOTCH.
    Marco Sciacovelli, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s41590-026-02528-0
  7. Nat Chem Biol. 2026 May 21.
    Cystine C-S bond cleavage fuels cysteine production under disulfide reductase deficiency.
    Edward E Schmidt, Eszter Petra Jurányi, Colin G Miller, Sydney A Austad, Tamás Ditrói, Zoe M Seaford, Sang Jun Yoon, Reed C Noyd, Yun Pyo Kang, Justin R Prigge, Vivien Csikós, Martina Serrano Alvarez, Katalin Erdélyi, Dóra Kővári, Gina M DeNicola, Peter Nagy.
      All organisms have thioredoxin reductase (TR) or glutathione reductase (GR), the only enzymes that use reduced nicotinamide adenine dinucleotide phosphate to reduce cytosolic disulfides into thiols, thereby powering deoxyribonucleotide biosynthesis, elimination of oxidants, oxidative damage repair and reduction of the disulfide nutrient cystine into the thiol amino acid cysteine. Hence, TR/GR-null bacteria or yeast are inviable; yet, remarkably, mice with TR/GR-null livers thrive, in part by synthesizing life-sustaining cysteine through alternative pathways that evolved in metazoans. Although TR/GR-null livers generate some of their cysteine through the serine transsulfuration pathway, we here show that most cysteine in TR/GR-null livers comes from a pathway in which pyridoxal-phosphate-dependent cleavage of a carbon-sulfur bond in cystine generates cysteine persulfide, which decomposes nonenzymatically into cysteine. This potent yet previously unrecognized pathway is regulated by cellular levels of sulfur metabolites and represents a potent cytoprotective response that might be induced in most mammalian cells under conditions that chronically elevate cytosolic cystine levels.
    DOI:  https://doi.org/10.1038/s41589-026-02213-1
  8. Annu Rev Nutr. 2026 May 19.
    Shaping Human Health and Nutrition Through Innovations in Spatial Metabolism.
    Craig W Vander Kooi, Matthew S Gentry, Ramon C Sun.
      Spatial metabolomics has emerged as a transformative approach for understanding how metabolism is organized within tissues and how nutritional factors influence health and disease. By preserving the spatial context of metabolites within intact tissue architecture, techniques such as MALDI and DESI imaging mass spectrometry reveal metabolic heterogeneity that bulk analyses cannot capture. This review examines how spatial metabolomics advances nutrition research across multiple domains: from mapping nutrient distributions in foods to understanding how diet reshapes tissue metabolism in disease states. We highlight recent innovations, including single-cell-resolution imaging, 3D metabolome reconstruction, stable isotope tracing, and multiomics integration. Key applications demonstrate how dietary patterns drive glycogen accumulation in cancer, alter lipid zonation in fatty liver disease, and modulate brain metabolism through the gut-brain axis. These spatially resolved insights establish direct mechanistic links between nutrition, tissue metabolism, and disease pathogenesis.
    DOI:  https://doi.org/10.1146/annurev-nutr-062024-111053
  9. Mitochondrion. 2026 May 16. pii: S1567-7249(26)00059-0. [Epub ahead of print] 102169
    Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
    Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.
      Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of vesicular structures across human biofluids, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy participants (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid to confirm enrichment. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary and largely qualitative results do not directly demonstrate but are consistent with the concept of mitochondria transfer and/or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.
    Keywords:  cell-free material; circulating; human; image repository; imaging; microscopy; mitochondria; study design; vesicles
    DOI:  https://doi.org/10.1016/j.mito.2026.102169
  10. Sci Immunol. 2026 May 29. 11(119): eaef0098
    Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
    Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.
      Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.
    DOI:  https://doi.org/10.1126/sciimmunol.aef0098
  11. Sci Adv. 2026 May 22. 12(21): eadz7896
    Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress.
    Michael C Mazzola, Ting Zhao, Anna Kiem, Trine A Kristiansen, Karin Gustafsson, Lai Ping Wong, Emily Scott-Solomon, Marissa D Fahlberg, Christina Mayerhofer, Ernst Mayerhofer, Sarah Forward, Emane Rose Assita, Giulia Schiroli, Maris Handley, Youmna Kfoury, Tsuyoshi Fukushima, Dan Li, Samuel Keyes, Azeem Sharda, Jelena Milosevic, Hiroki Kato, Pavel Ivanov, David B Sykes, Sheldon J J Kwok, Ruslan I Sadreyev, Vijay G Sankaran, Ya-Chieh Hsu, David T Scadden.
      Cell stress can increase the use of methylated guanosine (m7G) cap-independent, internal ribosome entry site (IRES)-mediated translation initiation relative to cap-dependent translation (IRES/Cap). Reporters that quantify IRES/Cap have demonstrated differential activity across cultured cell types and stress conditions. By generating an IRES/Cap reporter mouse, we were able to systematically evaluate IRES/Cap across distinct tissues and cell types during physiological stresses and lineage commitment. Caloric stress invoked the expected boost in IRES/Cap translation regardless of differentiation state, but unexpectedly, IRES/Cap progressively increased during hematopoietic and epithelial (hair follicle) differentiation under normal, homeostatic conditions. This was independent of total protein output or cell cycle. Even within cells of a given differentiation state, cells with lower relative IRES utilization had markedly higher multipotent capability in vivo. The RNA processing protein PTBP1 is a mediator of this translation initiation preference. Therefore, low IRES/Cap is a signature of high stemness and suggests that modulation of translation initiation participates in cell differentiation state.
    DOI:  https://doi.org/10.1126/sciadv.adz7896
  12. Mol Cancer. 2026 May 21.
    Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
    Luis Pardo, Madeleine Moore, Ruhi Deshmukh, Ian Powley, Joseph A Waldron, Bjorn Kruspig, Lynn McGarry, Lobsang Dolma, America V Campos, Colin Wood, Holly Leslie, Mark Hughes, Emanuel Jeldes, June Munro, Louise Mitchell, Leah Officer-Jones, Rachel Baird, Hugo Coquelet, Nigel B Jamieson, David Sumpton, Douglas Strathdee, John le Quesne, Martin Bushell, Daniel J Murphy, Jim C Norman.
       BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd).
    METHODS: We deployed autochthonous mouse models of LuAd driven by oncogenic KRASG12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients.
    RESULTS: Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRASG12D-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2+/+ lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2.
    CONCLUSIONS: Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.
    Keywords:  KRAS; Lung adenocarcinoma; Metabolism; Oncogene-induced senescence; Rapamycin; Trametinib; eIF4A; mRNA translation
    DOI:  https://doi.org/10.1186/s12943-026-02680-z
  13. bioRxiv. 2026 May 07. pii: 2026.05.05.722790. [Epub ahead of print]
    Acetyl-CoA Synthetase 1 regulates global histone propionylation and metabolic stress responses.
    Keith C Garcia, Chengjin Zhu, Ashby J Morrison.
      Cells and organisms are often exposed to various metabolic environments that require adaptive responses for survival. One common way cells adapt to fluctuating nutrient environments is through regulated transcription of metabolic genes. Intermediary metabolites, such as acetyl-CoA, produced by metabolic pathways, serve as cofactors for histone post-translational modifications, which in turn regulate gene expression. However, increasing evidence shows that non-acetyl acyl-CoAs, such as propionyl-CoA, participate in gene regulation during metabolic stress. In this report, we find that histone propionylation functions as a global response to glucose starvation. Furthermore, we find that Acetyl-CoA Synthetase 1 (Acs1) binds chromatin and is the primary enzyme responsible for generating propionyl-CoA in the nucleus. Together, our findings reveal that Acs1-mediated histone propionylation constitutes a novel pathway for metabolic adaptation, linking nutrient availability to chromatin modification.
    DOI:  https://doi.org/10.64898/2026.05.05.722790
  14. Genetics. 2026 May 18. pii: iyag126. [Epub ahead of print]
    Rhythmic Nuclear Import Mediated by Importins Regulates the Neurospora Circadian Clock.
    Ziyan Wang, Bin Wang, Bradley M Bartholomai, Jennifer J Loros, Jay C Dunlap.
      Circadian clocks in eukaryotes rely on precisely regulated negative feedback loops to generate daily rhythms. However, the delay mechanisms that extend this structurally simple feedback loop to ∼24 hours are not yet fully understood. In the filamentous fungal model organism Neurospora crassa, the negative arm complex, centered by FREQUENCY (FRQ), must enter the nucleus to repress the White Collar Complex (WCC) and close the feedback loop, but the mechanisms and dynamics of its nuclear transport have remained unresolved. Using long-term live-cell imaging and fluorescence recovery after photobleaching (FRAP), we demonstrate that FRQ nuclear import is an active circadian-regulated process that is fastest early in the subjective day and whose rate progressively decreases as nuclear FRQ approaches peak levels, corresponding to altered direct binding between FRQ and Importin α. We further establish that Importin α is required for the spatial regulation of FRQ and WCC, as well as the correct timing of Neurospora circadian clock, whereas the nuclear accumulation of non-clock-related free WC-2 doesn't require Importin α. Analysis of the three Neurospora Importin β homologs reveals that each of them contributes differently to the circadian clock through pathways beyond FRQ or WCC nuclear import. More specifically, we find a genetic interaction between Importin β3 and the phosphatase PPH-4. Together, these findings indicate that nuclear import is a selective, dynamic, and rate-limiting regulatory step in the fungal circadian clock and reveal both conserved and fungal-specific mechanisms by which importins tune circadian timing.
    Keywords:  FRAP; FREQUENCY (FRQ); Fluorescent live-cell imaging; White Collar Complex (WCC); fungi; nucleocytoplasmic transportation
    DOI:  https://doi.org/10.1093/genetics/iyag126
  15. Nat Commun. 2026 May 20.
    Endothelial Drp1 integrates VEGF-induced redox signaling with glycolysis through cysteine oxidation to drive angiogenesis.
    Sheela Nagarkoti, Young-Mee Kim, Archita Das, Dipankar Ash, Eric A Vitriol, Tracy-Ann Read, Varadarajan Sudhahar, Md Selim Hossain, Shikha Yadav, Stephanie Kelley Spears, Kelvin N Orji, Maritza J Romero, Rudolf Lucas, David Stepp, Eric J Belin de Chantemele, Ruth B Caldwell, David Jr Fulton, Tohru Fukai, Masuko Ushio-Fukai.
      Angiogenesis is essential for development and tissue repair after ischemia. Reactive oxygen species (ROS) act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly rely on aerobic glycolysis for energy production. However, how redox signaling couples to endothelial metabolism remains unclear. Here, we identify endothelial Drp1 as a redox sensor that links VEGF-induced H₂O₂ signaling to metabolic reprogramming and angiogenesis. Loss of Drp1 in ECs suppresses VEGF-driven angiogenic responses. Mechanistically, VEGF rapidly induces NOX4-dependent sulfenylation of Drp1 at Cys644, promoting disulfide bond with the metabolic kinase AMPK and subsequent oxidation of AMPK at Cys299/304 via mitochondrial fission-derived ROS. This pathway enhances endothelial glycolysis and angiogenesis. In vivo, mice with endothelial Drp1 deficiency or CRISPR-engineered redox-dead Drp1 (Cys to Ala) knock-in exhibit impaired retinal angiogenesis and post-ischemic neovascularization. Thus, endothelial Drp1 integrates mitochondrial redox signaling with glycolysis through cysteine oxidation-mediated Drp1-AMPK redox relay, thereby driving reparative neovascularization.
    DOI:  https://doi.org/10.1038/s41467-026-73128-7
  16. EMBO Rep. 2026 May 18.
    SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
    Yanlin Zi, Jiaqi Zhao, Miao Wang, Dan Hou, Richard A Cerione, Hening Lin.
      The ability to adapt to nutrient stress, such as amino acid limitation, is crucial for cell survival. The mTORC1 complex and integrated stress response (ISR) are two mechanisms that sense the availability of amino acids and regulate protein synthesis. Here, we reveal a new SIRT2-mediated pathway, downstream of the ISR, that is activated under amino acids limitation to suppress global translation. Under amino acid deprivation, SIRT2 protein level is upregulated translationally by its upstream open reading frame (uORF). SIRT2 in turn suppresses translation, which helps cells to survive amino acid limitation. We identify eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), which binds to eIF4E and inhibits translation, as a substrate of SIRT2. SIRT2 deacetylates 4E-BP1 at lysine 69 and stabilizes 4E-BP1 by protecting it from proteasomal degradation, leading to suppression of global translation. Our study uncovers a role for SIRT2 in regulating translation and identifies a new regulatory mechanism of 4E-BP1 in cells.
    DOI:  https://doi.org/10.1038/s44319-026-00803-7
  17. Nat Rev Drug Discov. 2026 May 18.
    Autophagy modulation in cancer.
    Emma Guilbaud, Kevin M Ryan, Douglas R Green, Lorenzo Galluzzi.
      Autophagy is a highly conserved, finely regulated and lysosome-dependent biological process through which eukaryotic cells mobilize metabolites in response to nutrient deprivation and dispose of supernumerary or toxic cytoplasmic entities to ensure cellular quality control. In line with the notion that autophagy globally preserves cellular homeostasis, defects in the molecular machinery for autophagy generally favour malignant transformation. Conversely, proficient autophagic responses are often beneficial to developing tumours as they support the survival of malignant cells facing harsh microenvironmental conditions. Finally, the ability of neoplastic cells to undergo autophagy influences their susceptibility to anticancer immune responses in a context-dependent manner. Thus, although autophagy stands out as a major target to intercept cancer at multiple inflection points of the disease, one-size-fits-all approaches are inherently incapable of capturing the complex influence of autophagy on the cancer cell (immuno)biology as a whole. Further complicating this scenario, healthy cells, including tumour-targeting immune effectors, rely on autophagy for their maturation, survival and functions, and pharmacological autophagy inhibitors currently available for use in humans are intrinsically nonspecific. Here, we discuss the promise and limitations of targeting autophagy to limit malignant transformation, exacerbate cancer cell death as driven by conventional therapeutics and restore immunosurveillance in support of superior disease responses to immunotherapy.
    DOI:  https://doi.org/10.1038/s41573-026-01449-9
  18. Nat Cell Biol. 2026 May 22.
    Stress granules shape ferroptosis in cancer.
    Maria Livia Sassano, Patrizia Agostinis.
      
    DOI:  https://doi.org/10.1038/s41556-026-01950-8
  19. Cancer Treat Res. 2026 ;195 237-247
    Tools and Technologies for Studying Cancer Metabolism.
    Ayush Madan, Subhajit Mandal, Soukat Chandra, Joy Das, Biplab Debnath.
      Tools for studying cancer metabolism include mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy for metabolomics, metabolic imaging (PET, MRI, MRS) for in vivo analysis, and metabolic flux analysis (MFA) with stable isotope tracers to track metabolic pathways. Other technologies involve microfluidic systems for simulating tumor environments and fluorescence-activated cell sorting (FACS)-based methods for analyzing immune cell metabolism. Multiple analytical platforms that facilitate the detection of metabolites in cells and living organisms have been utilized to study cancer metabolism. In this section, we will discuss how these techniques have contributed to the study of cancer metabolism and how they have led to advances in our understanding of metabolic reprogramming and biological phenotypes.
    Keywords:  Analytical platforms; Cancer metabolism; Metabolites
    DOI:  https://doi.org/10.1007/978-3-032-21861-2_12
  20. Nat Commun. 2026 May 19.
    Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.
    Junyu He, Meiqi Chen, Laiqin Peng, Qiqiong Wang, Yizhuang Lu, Yimin Chen, Xinyao Li, Yanling Mou, Jianjun Wang, Yuxiong Guo, Kai Wu, Yumei He.
      Group 3 innate lymphoid cells (ILC3) are crucial in neonatal necrotizing enterocolitis (NEC); however, the underlying mechanisms remain elusive. Here, we identify NKp46⁻CCR6⁻ (double-negative, DN) ILC3s as the dominant pathogenic subset driving NEC via IL-17 A secretion, which disrupts intestinal barrier integrity. Mechanistically, Atg5 activates autophagy in DN ILC3s during NEC. Atg5 conditional knockout in RORγt⁺ cells mitigates NEC, reduces DN ILC3 accumulation and IL-17 A production. Atg5 deficiency also decreases HIF-1α chromatin accessibility and transcriptional activity, shifting DN ILC3 metabolism from glycolysis to fatty acid oxidation. Lipidomics reveals phosphatidylcholine as a key downstream metabolite of Atg5-mediated autophagy. Phosphatidylcholine supplementation suppresses DN ILC3-driven inflammation, restores metabolic homeostasis, elevates Clostridium abundance, and ameliorates NEC in mice. Importantly, human NEC tissues exhibit increased ILC3 proportions, autophagic activity, and IL-17 A/IL-22 secretion. Thus, we uncover an Atg5-autophagy-glycolipid metabolic axis in DN ILC3s that drives NEC pathogenesis, providing a promising therapeutic target for neonatal NEC.
    DOI:  https://doi.org/10.1038/s41467-026-73356-x
  21. Redox Biol. 2026 May 16. pii: S2213-2317(26)00222-3. [Epub ahead of print]94 104224
    Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.
    Christos Chinopoulos.
      Respiratory chain limitation is a recurrent but spatially heterogeneous state in solid tumors, driven by hypoxic subregions, electron transport chain defects, and signaling- or therapy-imposed respiratory inhibition. Restricted electron flow supports an ETC-linked MRS state characterized by accumulation of reduced electron carriers and configuration-dependent reactive oxygen species formation. This review describes how electron transport chain limitation remodels posttranslational modifications through (i) oxygen partitioning and substrate control of oxygen-dependent dioxygenases -considering that respiratory complex IV is the dominant intracellular molecular oxygen sink, thus shaping its availability for hydroxylation and demethylation reactions- and (ii) redox backpressure that shifts NAD(P)+/NAD(P)H balance, perturbs acyl-CoA and citric acid cycle metabolite pools, and rewires protonmotive force-linked matrix chemistry and thiol buffering. These constraints are predicted to remodel lysine acylations, HIF hydroxylation, histone and DNA methylation, cysteine-centered redox PTMs, phosphorylation networks, ubiquitin-dependent proteostasis, ADP-ribosylation, and lactylation. Together, these relationships support a site- and context-dependent PTM-routing state in which the position of respiratory chain limitation and the local tumor environment shape which PTM chemistries become rate-limiting, adaptive, or growth-restrictive.
    Keywords:  Dioxygenases; Hypoxia; NAD(+)/NADH ratio; Reverse electron transfer; Sirtuins; Ubiquinone
    DOI:  https://doi.org/10.1016/j.redox.2026.104224
  22. Genome Biol. 2026 May 23.
    Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance.
    Ryan H Boe, Catherine G Triandafillou, Rossana Lazcano, Jennifer A Wargo, Arjun Raj.
      Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. We use spatial transcriptomics and single-cell RNA sequencing to uncover distinct resistance programs in melanoma cells shaped by intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization reveals shared intrinsic resistance programs across cell lines. In patient samples, these resistance programs coexist within individual tumors and associate with diverse immune signatures. Single-cell resolution spatial transcriptomics in xenograft models reveals both intrinsically determined and extrinsically influenced resistant fates. This work demonstrates that therapy-resistant fates coexist within distinct microenvironments and that tissue features influence which fate is adopted.
    DOI:  https://doi.org/10.1186/s13059-026-04112-z
  23. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  24. Biochem Soc Trans. 2026 May 27. 54(5): 585-599
    G0 or no-G0: phosphatase control of quiescence and cell cycle entry.
    Eleanor A Robinson, Alexis R Barr.
      During each cell cycle, cells must decide whether to continue to proliferate or to exit the cell cycle into a reversible arrest state, known as quiescence, or G0. This decision must be highly regulated to ensure proper tissue homeostasis. Studies on kinase-driven signalling pathways that regulate this decision point have dominated the field, and the role of phosphatases remains comparatively underexplored, yet the role of phosphatases is vitally important in signal transduction. In the present review, we examine how phosphatases contribute to the regulation of quiescence in mammalian cells across three stages: entry into quiescence, maintenance of the quiescent state, and quiescence exit into the cell cycle. We discuss how phosphatases counteract mitogenic signalling pathways, including MAPK/ERK and PI3K-AKT-mTOR, and maintain low cyclin-dependent kinase (CDK) activity through dephosphorylation of key cell cycle regulators, such as the retinoblastoma family proteins and CDK inhibitors. Finally, we highlight emerging evidence that dynamic regulation of phosphatase activity shapes the transition from quiescence back into proliferation. Understanding how phosphatases regulate the reversible nature of cell cycle arrest is important for understanding how tissues maintain homeostasis and how dysregulation of quiescence contributes to disease, including cancer.
    Keywords:  cell cycle; cell proliferation; protein phosphatases; quiescence; signalling
    DOI:  https://doi.org/10.1042/BST20250091
  25. Nat Commun. 2026 May 21.
    Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk.
    Kara M Barnao, Aubrey K Hubbard, Irenaeus C C Chan, Weiyin Zhou, Yasminka A Jakubek, Giulio Genovese, Wendy S W Wong, Rebecca L Kelly, Corey D Young, Derek W Brown, Wen-Yi Huang, Neal D Freedman, Kristine Jones, Amy Hutchinson, Belynda Hicks, Duc Tran, Donna Arnett, Kathleen C Barnes, Joshua C Bis, Eric Boerwinkle, Jennifer A Brody, April P Carson, Daniel I Chasman, Michael H Cho, Pinkal Desai, Margaret F Doyle, Myriam Fornage, Xiuqing Guo, Nancy Heard-Costa, Marguerite Ryan Irvin, Andrew D Johnson, Sharon L R Kardia, Charles Kooperberg, Daniel Levy, Joshua P Lewis, Yun Li, Ruth J F Loos, Taralynn M Mack, Rasika A Mathias, Braxton D Mitchell, Kari E North, Nathan Pankratz, Patricia A Peyser, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Albert V Smith, Jennifer A Smith, Adrienne Stilp, Yin Cao, Paul Scheet, Alexander P Reiner, Alexander G Bick, Stephen J Chanock, Paul L Auer, Kelly L Bolton, Mitchell J Machiela.
      Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.
    DOI:  https://doi.org/10.1038/s41467-026-73302-x
  26. bioRxiv. 2026 May 05. pii: 2026.05.01.722261. [Epub ahead of print]
    CPT1A loss promotes lung metastasis in immune-competent mice via a mechanism of mtDNA release and chronic activation of STING pathway.
    Xiaoyong Wang, Shu-Ting Chou, Yoonha Hwang, Jin Chen, Deanna N Edwards.
      The metastatic progression of breast cancer involves complex interactions between tumor cells and immune cells, including T cells that exert cytotoxic pressure to limit metastasis. Tumor cells reprogram their metabolism to evade immune surveillance, a critical step to achieving metastatic outgrowth. Using an unbiased CRISPR screen targeting metabolism-related genes and a clinically relevant spontaneous metastasis mouse model, we identified CPT1A, the rate-limiting enzyme in fatty acid β-oxidation, as a suppressor of immune-dependent metastasis. Loss of CPT1A enhances lung metastasis in immunocompetent mice, but not Rag1 KO mice that lack mature lymphocytes. Loss of CPT1A triggers cytosolic mitochondrial DNA (mtDNA) release via the mPTP pore. Cytosolic mtDNA release triggers a STING-dependent inflammatory response, creating an environment that impairs CD8+ T cell function, promoting metastatic outgrowth. Among breast cancer patients, low CPT1A expression correlates with poor survival when CD8+ T cell infiltration is high. These findings reveal an extrinsic role for CPT1A in immune-tumor dynamics and suggest therapeutic opportunities targeting inflammation in metastatic breast cancer.
    DOI:  https://doi.org/10.64898/2026.05.01.722261
  27. Blood Red Cells Iron. 2025 Dec;pii: 100020. [Epub ahead of print]1(3):
    GPX4 regulates lipid peroxidation and ferroptosis of stored red blood cells.
    Daniel Stephenson, Gregory R Keele, Ariel Hay, Monika Dzieciatkowska, Julie A Reisz, Zachary B Haiman, Amy L Moore, Travis Nemkov, Xutao Deng, Mars Stone, Kirk C Hansen, Steven Kleinman, Philip J Norris, Michael P Busch, Gary A Churchill, Brent R Stockwell, Nareg Roubinian, James C Zimring, Grier P Page, Angelo D'Alessandro.
      Red blood cell (RBC) membrane lipid peroxidation during blood bank storage profoundly impacts transfusion efficacy; however, the genetic determinants underlying RBC resilience remain incompletely defined. Here, we identify a critical role for glutathione peroxidase 4 (GPX4) - a pivotal enzyme protecting against iron-dependent lipid peroxidation (ferroptosis) - in regulating RBC storage quality and post-transfusion survival. Conditional erythroid-specific deletion of Gpx4 in mice exacerbated lipid hydroperoxide accumulation, oxidation and ubiquitination of membrane proteins, and reduced RBC recovery after transfusion. Multi-omics analyses in 13,091 human blood donors from the REDS RBC Omics cohort identified regulatory intergenic (rs8178962), intronic and missense genetic variants in GPX4 (rs73507255, rs8178967), particularly prevalent among donors of African descent, that were linked to increased lipid peroxidation and compromised post-transfusion hemoglobin increments. Single protein- and metabolome-wide association studies (pQTL/mQTL) highlighted genetic variants associated with enhanced (rs8178962) or impaired GPX4 expression, disrupted glutathione homeostasis, lipid hydroperoxide accumulation, accelerated membrane damage, and activation of ferroptotic signatures during RBC storage. These effects were exacerbated by genetic traits impairing redox homeostasis, including glucose 6-phosphate dehydrogenase (G6PD) deficiency (African variant rs1050828 V68M/N126D). Storage of murine RBCs in presence of the ferroptosis inhibitor ferrostatin-1 prevented storage-induced lipid peroxidation and boosted post-transfusion recovery, a beneficial effect in part phenocopied by supplementation of lipophilic antioxidants vitamin E and Lands cycle fueling via L-carnitine, and in part ablated by GPX4 inhibition via the covalent inhibitor ML210. This study offers mechanistic insights into RBC ferroptosis and positions GPX4 genetic status as a promising biomarker for precision transfusion medicine.
    Keywords:  Glutathione; hemolysis; precision transfusion medicine; transfusion
    DOI:  https://doi.org/10.1016/j.brci.2025.100020
  28. Cell Rep Methods. 2026 May 22. pii: S2667-2375(26)00162-1. [Epub ahead of print] 101462
    Atomic elementary flux modes explain the steady state flow of metabolites in large-scale flux networks.
    Justin G Chitpin, Theodore J Perkins.
      Steady state fluxes are a measure of cellular activity under homeostatic conditions, but understanding how individual substrates are metabolized remains a challenge in large-scale networks. Pathway-based approaches such as elementary flux mode (EFM) analysis are limited to small networks due to the combinatorial explosion of pathways and ambiguity of decomposing fluxes onto EFMs. Here, we present an alternative approach explaining metabolic fluxes in terms of the steady state flow of their atomic constituents. We refer to these pathways as atomic elementary flux modes (AEFMs) and show that computations involving AEFMs are orders of magnitude faster than standard EFMs. Using our approach, we enumerate carbon and nitrogen AEFMs in five genome-scale metabolic models and compute the AEFM decomposition of fluxes estimated in a HepG2 liver cancer cell line. Our results systematically characterize carbon and nitrogen remodeling and, on the HepG2 network, predict glutamine metabolism through a recently discovered non-canonical tricarboxylic acid (TCA) cycle.
    Keywords:  CP: computational biology; CP: metabolism; Markov chain; elementary flux mode; flow decomposition; flux network; metabolic pathway; steady state flux
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101462
  29. Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00799-9. [Epub ahead of print]
    NRF2 Coordinates Ferroptosis and Disulfidptosis in Dermal Papilla Cells via Redox Metabolic Reprogramming in Androgenetic Alopecia.
    Xiaowen Mao, Wenwen Zhou, Weiyi An, JieZhi Zhang, Honglin Chen, Mang Sun, Hengguang Zhao.
      Dysfunction of dermal papilla cells (DPCs) is a central feature of androgenetic alopecia (AGA), in which oxidative imbalance plays a critical role. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular redox homeostasis; however, its role in AGA remains unclear. Here, using primary DPCs, hair follicle organoids, and dihydrotestosterone (DHT)-induced mouse models, we found that NRF2 was markedly downregulated under AGA-associated conditions. Mechanistically, our data suggest that reduced NRF2 activity is associated with two distinct regulated cell death-related processes in DPCs: ferroptosis and disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF), together with molecular and metabolic analyses, indicated that impaired NRF2 signaling was linked to suppression of the SLC7A11-GSH-GPX4 axis, increased lipid peroxidation, and ferroptosis-related injury. In parallel, reduced NRF2 activity was associated with impaired pentose phosphate pathway (PPP) activity, NADPH depletion, disulfide stress, cytoskeletal disruption, and features consistent with disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF) effectively attenuates both ferroptosis and disulfidptosis, restoring hair follicle structure and promoting hair growth in AGA models. Collectively, our findings identify NRF2 as a central regulator linking redox metabolism to ferroptosis and disulfidptosis in DPCs, and highlight NRF2 activation as a potential therapeutic strategy for AGA.
    Keywords:  Androgenetic alopecia; Disulfidptosis; Ferroptosis; NRF2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.313
  30. Nat Immunol. 2026 May 21.
    Mapping where mouse models match - and miss - human tumor immunity.
      
    DOI:  https://doi.org/10.1038/s41590-026-02527-1
  31. Mol Cell. 2026 May 22. pii: S1097-2765(26)00271-6. [Epub ahead of print]
    In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging.
    Clara Duré, Umesh Ghoshdastider, Ramona Weber, Ameya Khandekar, Fabiola Valdivia-Francia, Peter F Renz, Federica Sella, Katie Hyams, David Taborsky, Merve Yigit, Mark Ormiston, Homare Yamahachi, Mitchell Levesque, Stephanie J Ellis, Ataman Sendoel.
      Somatic stem cells are characterized by their low overall protein-synthesis rates, a feature implicated in driving their stemness. However, how aging reshapes the translational landscape of stem cells remains poorly understood. Here, we present an in vivo single-cell ribosome profiling strategy to monitor tissue-wide translational landscapes of the epidermis during aging. By implementing ribosomal elongation-inhibited cell isolation and switching to RNase I, we expand the applicability of single-cell ribosome profiling to in vivo systems and facilitate the evaluation of triplet periodicity, a hallmark of high-quality data. Leveraging this strategy, we document the in vivo translational landscapes of the major epidermal cell types, outline cell-type-specific translational efficiencies, and identify a pronounced translational reprogramming of AP-1 subunits specifically in aged epidermal stem cells. Our study illustrates the power of in vivo single-cell ribosome profiling to map cell-type-specific translational programs and offers a scalable strategy for tissue-wide interrogation of translational landscapes.
    Keywords:  AP-1; aging; epidermis; mRNA translation; ribosome profiling; single-cell biology; translational control
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.017
  32. Trends Cell Biol. 2026 May 18. pii: S0962-8924(26)00067-X. [Epub ahead of print]
    Biophysical principles of cell competition and elimination.
    Andreas Schoenit, René-Marc Mège, Benoît Ladoux.
      Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.
    Keywords:  cell competition; cell extrusion; epithelia; force transmission; tissue mechanics
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.009
  33. Nat Commun. 2026 May 18.
    Mpi-driven N-glycosylation orchestrates mucin O-glycosylation and intestinal homeostasis.
    Avishek Roy, Steve Meregini, Hye-Jeong Cho, Zhenglan Chen, Aariz Zaki, Tandav Argula, Bruce Beutler, Jeffrey A SoRelle.
      The intestinal mucus barrier physically separates the epithelium from the dense microbial community of the gut and is essential for intestinal homeostasis. The principal component, the gel-forming mucin MUC2, is extensively glycosylated, yet how different classes of glycans regulate mucin function remains unclear. Here we show that N-glycosylation is required for proper MUC2 maturation and mucus barrier integrity. Using mouse models with hypomorphic or intestinal epithelial-specific loss of the mannose-generating enzyme MPI, which is required for N-glycan synthesis, we find that impaired N-glycosylation disrupts mucin processing and secretion. MPI deficiency results in severe susceptibility to dextran sulfate sodium-induced colitis or spontaneous intestinal inflammation, accompanied by endoplasmic reticulum stress, microbial dysbiosis, and defects in Paneth cells. These findings demonstrate N-glycosylation is critical for mucus barrier function and reveal an unexpected link between N-glycosylation and intestinal inflammatory disease.
    DOI:  https://doi.org/10.1038/s41467-026-73100-5
  34. Nat Metab. 2026 May 22.
    Glycerol is a new ally for heat production and bone health.
    Ambre M Bertholet.
      
    DOI:  https://doi.org/10.1038/s42255-026-01545-5
  35. Nature. 2026 May 20.
    Too little or too much sleep is linked to faster ageing throughout the body.
      
    Keywords:  Ageing; Diseases
    DOI:  https://doi.org/10.1038/d41586-026-01564-y
  36. Cell. 2026 May 19. pii: S0092-8674(26)00508-8. [Epub ahead of print]
    Genome instability triggers intercellular DNA transfer between human cells.
    Elizabeth G Maurais, Alice Mazzagatti, Yu-Fen Lin, Maria Narozna, Qing Hu, Rashmi Dahiya, Derek Santiago-Ferrer, Conor P Herlihy, Mary Krebs, Nikoleta Pateraki, Evlampia Parcharidou, Stamatis Papathanasiou, Brian J Beliveau, Gary J Gorbsky, Isidro Cortés-Ciriano, Peter Ly.
      The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell-autonomous consequences to nearby cells remains unclear. Here, we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability-including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage-promote nanotube-mediated DNA transfer in both cancerous and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal genetic elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes.
    Keywords:  DNA damage; chromothripsis; cytoplasmic DNA; ecDNA; genomic instability; horizontal gene transfer; intercellular transfer; micronuclei; mitosis; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2026.04.041
  37. mSystems. 2026 May 18. e0027626
    Metabolic robustness is an emergent property of hierarchical network organization in yeast.
    Mohammad Tauqeer Alam.
      Biological systems exhibit intrinsic robustness, allowing cells to sustain growth despite diverse perturbations. We quantified the inherent robustness of the Saccharomyces cerevisiae genome-scale metabolic network by globally perturbing metabolite production fluxes using a hypothetical sink reaction. Among the 317 high-flux active metabolites, excluding macromolecular intermediates and highly connected cofactors, 85% were found to be robust. Of these robust metabolites, more than half (144/269) were overproduced under perturbation compared with minimal-media controls. These metabolites, mapped to a single central metabolic cluster within the metabolic network, were enriched in core biosynthetic pathways and were largely growth-essential, indicating that the network tolerates elevated biosynthetic demand for most key metabolites. Flux- and pathway-level analyses revealed a coordinated adaptive program involving activation of alternative routes at the network periphery and extensive flux redistribution within central metabolism. Central carbon metabolism and oxidative phosphorylation were broadly suppressed, whereas the pentose phosphate, shikimate, and lipid-related pathways were selectively reinforced to support NADPH generation and redox balance. This reorganization establishes an energy-efficient, redox-stabilized metabolic state that underlies system-wide resilience. Together, these findings show that metabolic robustness emerges from a hierarchical network architecture coupling a stable core with flexible peripheral adaptation. This framework explains cellular resilience and offers design principles for engineering robust, damage-resistant metabolic systems.IMPORTANCEIn this study, we investigated the intrinsic robustness of the metabolic network and uncovered a structured organization characterized by a conserved central core and a flexible, peripherally rewired subsystem. Our results suggest that this architecture reflects an evolutionary balance between stability and adaptability. By systematically perturbing more than 300 metabolites, we provide comprehensive and consistent evidence supporting the existence of this core-periphery organization. These findings advance our understanding of how metabolic systems maintain functional stability while retaining the capacity for adaptive rewiring.
    Keywords:  adaptation; flux reprogramming; metabolic network; robust metabolite; robustness; systems biology
    DOI:  https://doi.org/10.1128/msystems.00276-26
  38. Trends Immunol. 2026 May 16. pii: S1471-4906(26)00101-8. [Epub ahead of print]
    Rethinking the origins and functions of adaptive immunity.
    Derick Okwan-Duodu, Erik A Sperling, Edgar G Engleman.
      The adaptive immune system (AIS) is traditionally viewed as a defensive vertebrate innovation forged by pathogen pressure. Yet many of its core features suggest it is a homeostatic, regulatory circuit, not simply a sophisticated means of antimicrobial warfare. The horizontal transfer of mitochondria--endogenous endosymbiotic organelles-is a conserved mechanism for maintaining tissue homeostasis through metabolic rescue but can alter a cell's identity and provoke immune responses. We propose that escalating multicellular complexity accommodated mitochondrial mobility-and the inevitable intrinsic immunological danger it presents-through a complementary supervisory system with buffering (tolerance), contextualization (specificity), memory, and eliminatory capacities. This perspective reframes the AIS as a constitutive danger management network, integrating tissue homeostasis, metabolic surveillance, immune tolerance, and immunological defense.
    Keywords:  constitutive danger; horizontal mitochondria transfer; immunity; tissue homeostasis; tolerance
    DOI:  https://doi.org/10.1016/j.it.2026.04.008
  39. Neuron. 2026 May 19. pii: S0896-6273(26)00330-2. [Epub ahead of print]
    ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis.
    Jorge Gómez-Deza, Matthew Nebiyou, Lara H El Touny, Mor R Alkaslasi, Zhenyu Zuo, Josette J Wlaschin, Francisco M Nadal-Nicolás, Alexandra Stavsky, Xiaotian Zhang, Anastasia L Slavutsky, Ariel Y Zhang, Eliza Y H Lloyd, Peter M Hayashi, Nathan Ashby, Mariella G Brueck, Mira Sohn, Ryan K Dale, Gareth M Thomas, Wei Li, Ken Chih-Chien Cheng, Pedro P Rocha, Claire E Le Pichon.
      Neuronal apoptosis is a key feature of neurodegenerative diseases. Considerable efforts have been made to target this pathway; however, the underlying molecular mechanisms remain incompletely understood. Here, we conducted an unbiased, genome-wide CRISPR inhibition screen in human neurons to discover genes required for cell death. We uncover a multitude of targets required for neuronal apoptosis, some known and many previously unidentified. Among them, three stood out as members of a pro-death cascade: dual leucine zipper kinase (DLK or MAP3K12) and the transcription factors JUN and the lesser-known activating transcription factor 2 (ATF2). Through mechanistic studies, we demonstrate that ATF2 phosphorylation by MAP3 kinases is a critical step in neuronal apoptosis. Surprisingly, JUN phosphorylation is not required. Conversion of the MAP3 kinase signal into a pro-apoptotic transcriptional response requires phospho-ATF2 to upregulate JUN. We show that interfering with ATF2 function prevents neuronal apoptosis in vitro and in vivo. Our work posits ATF2 as a promising target for a wide range of neurodegenerative disorders.
    Keywords:  ATF2; CRISPRi screen; DLK; JUN; LZK; MAP3K12; cytoskeletal stress; neuron death; neuron injury signaling; neuronal apoptosis
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.035
  40. Nat Commun. 2026 May 19.
    High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities.
    Grand Challenges PRECISION Consortium
      Ductal carcinoma in situ is a non-obligate precursor lesion of breast cancer. Often detected by mammography, most cases are managed through surgical and/or radiotherapy approaches. Today, it is not possible to predict which patients will progress to invasive disease. Here, we evaluate high-depth whole-genome sequenced ductal carcinoma in situ, enriched for high-grade clinical lesions, to understand whether deep WGS could reveal biological insights and/or personalized therapeutic vulnerabilities that may be targetable. We find genomic locations that are likely susceptible to producing the initiating lesion for structural variations prone to subsequent evolution, termed SHOREs. We additionally highlight individualized therapeutic potential that would otherwise not be appreciable without whole genome sequencing. We posit that holistic whole genome sequencing profiling could offer a more precise stratification approach, discerning higher-risk cases for prospective clinical studies on personalized therapies, from truly low-risk cases suitable for active monitoring.
    DOI:  https://doi.org/10.1038/s41467-026-72952-1
  41. bioRxiv. 2026 May 06. pii: 2026.05.02.722429. [Epub ahead of print]
    PBRM1-VHL cooperation rewires lipid and iron metabolism to promote ferroptosis resistance in clear cell renal cell carcinoma.
    Guanming Jiao, Luisa F Baracaldo-Lancheros, Alisha Dhiman, Christina R Ferreira, Emily C Dykhuizen.
      Clear cell renal cell carcinoma (ccRCC) is initiated by biallelic loss of the tumor suppressor VHL followed by additional genomic alterations, including loss of tumor suppressors PBRM1, BAP1 or SETD2. Although ccRCC is known to be intrinsically sensitive to ferroptosis, the contribution of PBRM1 to this vulnerability, and how it interfaces with VHL loss, has remained unexplored. Using isogenic ccRCC and non-transformed cell models, we show that re-expression of PBRM1 and/or VHL attenuates GPX4-inhibitor-induced ferroptosis, and that the two tumor suppressors act cooperatively: dual reconstitution confers the greatest protection, suppresses lipid peroxidation, and preserves redox homeostasis. Time-resolved RNA-seq reveals that PBRM1 and VHL establish additive, largely non-overlapping "ground-state" transcriptional programs. Integrated pharmacogenomic, CRISPR dependency, and lipidomic analyses converge on two protective axes: restricted labile iron and MUFA-biased membrane remodeling. These findings identify PBRM1 as a previously unrecognized modulator of ferroptosis and define a cooperative chromatin-metabolic axis that buffers ferroptotic cell death in ccRCC.
    DOI:  https://doi.org/10.64898/2026.05.02.722429
  42. Nat Aging. 2026 May;6(5): 961-969
    From whole-body to organ-specific biological age clocks.
    Andrew Zalesky, Junhao Wen, Ye Ella Tian.
      Recent work leveraging omics and imaging data now enables the estimation of aging at the level of individual organs. Emerging findings suggest that organs age at different rates, which may be linked to environmental exposures and genetic factors. However, premature aging in one organ may also drive aging in connected organs within multi-organ aging networks. Here, we outline methods for measuring organ-specific biological age and discuss insights derived from recent progress in multi-organ aging research. We put forward recommendations, best practices and research priorities, including the importance of longitudinal tracking, biomarkers with high organ specificity and reference ranges for organ age gaps. We envision routine organ-specific biological age assessments as tools for developing personalized organ aging maps and tracking organ aging across the life course, thereby facilitating early, targeted interventions to delay organ-specific decline and interorgan consequences.
    DOI:  https://doi.org/10.1038/s43587-026-01113-2
  43. Cancer Immunol Immunother. 2026 May 20.
    β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses.
    Yupan Bai, Han Xue, Yujie Bao, Yue Pan, Jiayin Tang, Mengna Wang, Ying Wang, Jie Xu, Jing Huang.
      Ketogenic diets (KDs) have been reported to influence tumor progression through metabolic and immunological modulation of the tumor microenvironment. β-hydroxybutyrate (βOHB), the predominant ketone body elevated by KD, functions not only as an energy substrate but also as a potent signaling metabolite. Despite its role in modulating the tumor microenvironment, the direct impact of βOHB on the function of CD8+ T cell, a key mediator of anti-tumor immunity, remains incompletely understood. Here, we demonstrate that βOHB suppresses tumor growth in multiple mouse tumor models by enhancing the accumulation, survival, and effector function of tumor-infiltrating CD8+ T cells. In contrast, acetoacetate does not exert comparable immunomodulatory effects. Mechanistically, βOHB upregulates the Tcf7-Lck signaling pathway by engaging with the cell surface receptor Hcar2, an effect potentially working in parallel with its role as an HDAC inhibitor. Knockdown of either Tcf7 or Hcar2 in CD8+ T cells abolishes the promoting effect of βOHB on CD8+ T function. Our findings elucidate a metabolite-immune axis that directly regulates the functional state of tumor-infiltrating CD8⁺ T cells and provide experimental evidence linking ketone metabolism to anti-tumor immune regulation.
    Keywords:  Anti-tumor therapy; CD8+ T cell; Lck; Tcf7; β-hydroxybutyrate
    DOI:  https://doi.org/10.1007/s00262-026-04420-0
  44. bioRxiv. 2026 May 08. pii: 2026.05.07.723605. [Epub ahead of print]
    Localized heme sensing through a ternary molecular glue.
    Michael Heider, Clara Hipp, Zhi Yang, Han Xiao, Tobias Beschauner, Eddie Wehri, Wencke Walter, Rumi Sherriff, Srividya Chandrasekhar, Torsten Haferlach, Julia Schaletzky, Michael Rape.
      Molecular glues are an emerging class of therapeutics that stabilize binary interactions and thereby rewire disease-relevant protein networks. Whether glues can integrate additional information to orchestrate signaling beyond initial complex formation is unknown. Here, we report that cells use an endogenous glue strategy to sense heme, an essential metabolite with deleterious pro-oxidant properties. Distinct from other glues, heme bridges three polypeptides to trigger degradation of the transcriptional repressor BACH1 through cytoplasmic, but not mitochondrial, CUL2FEM1B. This mechanism allows cells to eliminate toxic heme in the cytoplasm by inducing expression of the heme-degrading oxygenase HMOX1, yet ignore mitochondrial heme destined for function in the electron transport chain. While protective in healthy cells, ternary glue signaling creates a therapeutic vulnerability for Acute Myeloid Leukemias dependent on high rates of ETC assembly. Molecular glues can therefore drive assembly of higher-order complexes to establish localized signaling, which offers unexplored opportunities for induced proximity therapeutics.
    DOI:  https://doi.org/10.64898/2026.05.07.723605
  45. EMBO J. 2026 May 20.
    Autoinhibitory feedback preserves intestinal stem cell maintenance and fate commitment.
    Siamak Redhai, Nick Hirschmüller, Tianyu Wang, Tyler Jackson, Stefan Peidli, Erica Valentini, Shivohum Bahuguna, Svenja Leible, Sarina Möller, Christina Ko, Michaela Holzem, Sviatoslav Kharuk, Lea Bräckow, Fillip Port, David Ibberson, Hongjie Le, Wolfgang Huber, Michael Boutros.
      Intestinal stem cells (ISCs) continuously renew the gut epithelium by producing specialised cell types, yet the mechanisms that couple ISC renewal with lineage commitment remain poorly characterised. Here, we identify a self-limiting transcriptional program, mediated by the zinc-finger transcription factor Chronophage (Cph), that promotes both ISC maintenance and differentiation into enteroendocrine (EE) cells in the Drosophila midgut. Cph expression is transiently induced by the proneural factor scute at the onset of ISC-to-EE specification. Genetic and single-cell transcriptomic approaches revealed that Cph is required to reprogramme ISCs and sustain normal lifespan. Cph binds to genes involved in proliferation and differentiation, and directly represses its own expression. This autoinhibitory feedback safeguards ISCs from accumulating autophagosomes and undergoing cell death, thus preserving ISC function. Our findings uncover a key regulatory mechanism that balances stem cell maintenance and differentiation, highlighting principles relevant to regenerating tissues.
    DOI:  https://doi.org/10.1038/s44318-026-00808-x
  46. Nat Methods. 2026 May 22.
    A multimodal adaptive optical microscope for in vivo imaging from molecules to organisms.
    Tian-Ming Fu, Gaoxiang Liu, Daniel E Milkie, Xiongtao Ruan, Frederik Görlitz, Yu Shi, Valentina Ferro, Nikita S Divekar, Wei Wang, Harrison M York, Velat Kilic, Matthew Mueller, Yajie Liang, Timothy A Daugird, Maria Jose Gacha-Garay, Kathryn A Larkin, Rebecca C Adikes, Nathanael Harrison, Cyna Shirazinejad, Samara Williams, Jamison L Nourse, Shu-Hsien Sheu, Liang Gao, Tongchao Li, Chandrani Mondal, Kemal Achour, Wilmene Hercule, Daniel R Stabley, Kevin Emmerich, Peng Dong, David G Drubin, Zhe J Liu, Jeff S Mumm, Minoru Koyama, Alison N Killilea, Jose Javier Bravo-Cordero, C Dirk Keene, Liqun Luo, Tomas Kirchhausen, Medha M Pathak, Senthil Arumugam, James K Nuñez, Ruixuan Gao, David Q Matus, Benjamin L Martin, Ian A Swinburne, Eric Betzig, Wesley R Legant, Srigokul Upadhyayula.
      Understanding biological systems requires observing features and processes across vast spatial and temporal scales, spanning nanometers to centimeters and milliseconds to days, often using multiple imaging modalities within complex native microenvironments. Yet, achieving this comprehensive view is challenging because microscopes optimized for specific tasks typically lack versatility due to inherent optical and sample handling tradeoffs, and frequently suffer performance degradation from sample-induced optical aberrations in multicellular contexts. Here, we present Multimodal Optical Scope with Adaptive Imaging Correction (MOSAIC), a reconfigurable microscope that integrates multiple advanced imaging techniques including light-sheet, label-free, super-resolution and multiphoton, all equipped with adaptive optics. MOSAIC enables noninvasive imaging of subcellular dynamics in both cultured cells and live multicellular organisms, nanoscale mapping of molecular architectures across millimeter-scale expanded tissues and structural/functional neural imaging within live mice. MOSAIC facilitates correlative studies across biological scales within the same specimen, providing an integrated platform for broad biological investigation.
    DOI:  https://doi.org/10.1038/s41592-026-03066-1
  47. Oncogenesis. 2026 May 20.
    Metabolic vulnerabilities in pleural mesothelioma.
    Sílvia Plans-Marin, Cristina Muñoz-Pinedo, Ernest Nadal.
      Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma's aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.
    DOI:  https://doi.org/10.1038/s41389-026-00625-1
  48. Cell. 2026 May 19. pii: S0092-8674(26)00505-2. [Epub ahead of print]
    Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.
    Ya-Hsuan Ho, Giacomo Bregni, Marco Stazi, Paola Peinado, Pei-Hsing Chen, Claudio Ballabio, Victoire Boulat, Shree Vadera, Yilin Guan, Zhikai Liu, Alicia Alonso de la Vega, Li Wang, Chao-Chi Ho, Henrique Veiga-Fernandes, Julian Downward, Min-Shu Hsieh, Maksym V Kopanitsa, George Kassiotis, Christoforos Tsantoulas, Michael S Schappe, Michael-Bogdan Margineanu, Dinis Pedro Calado, Isaac M Chiu, Charles Swanton, Jin-Shing Chen, Leanne Li.
      Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13+ fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.
    Keywords:  CGRP; cancer immunology; cancer neuroscience; chemogenetics; cigarette smoking; genetically engineered mouse model; lung adenocarcinoma; macrophage; neuroimmune crosstalk; non-small cell lung cancer; sensory neuron; tertiary lymphoid structure
    DOI:  https://doi.org/10.1016/j.cell.2026.04.038
  49. Nat Commun. 2026 May 20.
    Glucuronidation metabolomic fingerprinting to map host-microbe metabolism.
    Nina R Boyle, Josh J Sekela, Mingxun Wang, Helena Mannochio-Russo, Jeong Joo Pyo, Min Soo Kim, Shuchang Tian, Imhoi Koo, Elliot S Friedman, Ceylan Tanes, Mallappa Anitha, Yuan Tian, Ethan W Morgan, Iain A Murray, Joseph P Zackular, Kyle Bittinger, James D Lewis, Gary H Perdew, Gary D Wu, Babette S Zemel, Pieter C Dorrestein, Jordan E Bisanz, Matthew R Redinbo, Andrew D Patterson.
      Glucuronidation is an important detoxification pathway that operates in balance with gastrointestinal microbial β-glucuronidase (GUS) activity, which can regenerate bioactive metabolites from their glucuronidated forms. How this host-microbe interaction shapes the distribution and pool of glucuronidated metabolites (i.e., the glucuronidome) remains poorly understood. In this study, we employed pattern-filtering data science approaches in conjunction with untargeted LC-MS/MS metabolomics to map the glucuronidome in urine, serum, and colon/fecal samples from gnotobiotic and conventional mice, and in humans. We find that microbial colonization and GUS activity compress the colonic glucuronidome and expand urinary glucuronidome diversity, revealing a compartmental redistribution of glucuronidated metabolites. Reverse metabolomics of known glucuronidated chemicals and glucuronidation pattern filtering searches in public metabolomics datasets exposed the diversity of glucuronidated metabolites in human and mouse ecosystems. In summary, we present a glucuronidation fingerprint resource that provides broader access to and analysis of the glucuronidome. Together, this work establishes a scalable analytical framework and provides mechanistic insight into how microbial activity reshapes systemic glucuronidation, with implications for drug metabolism, diet-microbe interactions, and biomarker discovery.
    DOI:  https://doi.org/10.1038/s41467-026-73398-1
  50. Cell Rep. 2026 May 21. pii: S2211-1247(26)00509-7. [Epub ahead of print]45(6): 117431
    MIF mediates monocyte-dependent inhibition of natural killer cell cytotoxicity in triple-negative breast cancer.
    Christos Ermogenous, Marti Brucoli, Alessandra Perini, Adriana Yunda de Miguel, Rithu Kumar, Jaume Barcelo, Maddy Boardman, Mahima Grover, Gordon Beattie, Aikaterini Kafka, Luigi Ombrato.
      Immunotherapies remain ineffective in triple-negative breast cancer (TNBC), underscoring the need to define drivers of immune suppression. Natural killer (NK) cells are crucial for eliminating disseminated tumor cells (DTCs) through NK cell cytotoxicity (NKCC), but this is impaired in metastasis. While tumor cell-intrinsic mechanisms of NK cell evasion are known, the role of other cells in the tumor microenvironment remains unclear. Using the Cherry-niche labeling system, we profiled early TNBC lung micrometastases and identified bone marrow-derived monocytes to be highly enriched and capable of suppressing NK cells within metastatic niches. Functional studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) suppresses NKCC against TNBC cells via CXCR4. MIF inhibition restored NK cell activatory receptors, cytotoxic mediators, and tumor cell killing in vitro, while reducing metastatic outgrowth and increasing NK cell activatory receptors in vivo. These findings reveal MIF as a potential target to enhance NK cell function in TNBC metastasis.
    Keywords:  CP: cancer; CP: immunology; CXCR4; MIF; NK cells; NKCC; TME; TNBC; macrophages; metastasis; monocytes
    DOI:  https://doi.org/10.1016/j.celrep.2026.117431
  51. bioRxiv. 2026 May 09. pii: 2026.05.07.723592. [Epub ahead of print]
    Metabolic Coherence of the Mouse Brain.
    Zizhen Liu, Xin Ma, Roberto A Ribas, Terrymar Medina, Sadi Quinones, Jihye Son, Lei Wu, Alison M Ryan, Cameron Shedlock, Borhane Ziani, Vicenzo Barco-Caiaffa, Nidhi Rao, Kangjin Wong, Ann Titus, Reece Larson, Craig W Vander Kooi, Navdeep S Chandel, Matthew S Gentry, Li Chen, Ramon C Sun.
      The brain's metabolic demands are well established, but how metabolism is coordinated across anatomically distinct regions remains poorly understood. Here, using matrix-assisted laser desorption/ionization (MALDI) imaging integrated with the Allen Brain Atlas and optimal transport-based computational analysis, we map the spatial metabolome across twelve major mouse brain divisions. We define an optimal-transport-derived inter-regional metabolite similarity metric and refer to it as metabolic coherence. This structure is largely preserved in an amyloid mouse model of Alzheimer's disease despite widespread changes in individual metabolite and lipid levels. Individual metabolites and lipids shift in a coordinated manner across regions, sustaining inter-regional relationships even as absolute levels change in patterns indicative of mitochondrial dysfunction. To test whether the coherence metric is responsive to local intervention, we targeted the left hippocampus of mice from this model via lentiviral shHIF1α knockdown or neuronal AAV-mediated AOX expression. Both interventions were associated with metabolite normalization at the injection site. More importantly, normalization extended across distal regions sharing high metabolic similarity with the hippocampus and was accompanied by improved social memory in a single behavioral assay. Gene modulation and amyloid plaque reduction localized to the injection site.
    DOI:  https://doi.org/10.64898/2026.05.07.723592
  52. Elife. 2026 May 21. pii: RP109093. [Epub ahead of print]14
    Lipopolysaccharide stimulates dynamic changes in B cell metabolism to promote proliferation.
    Dana M S Cheung, Momchil Razsolkov, Fabrizia Bonacina, Stephen Andrews, Megan C Sumoreeah, Linda V Sinclair, Andrew J M Howden, J Simon C Arthur.
      Naive B cells exit quiescence and enter a proliferative state upon activation, ultimately differentiating into antibody-secreting or memory B cells. Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS), can serve as physiological stimuli to initiate this transition. Using quantitative proteomics, we show that TLR4 engagement induces metabolic reprogramming in murine B cells, increasing the expression of amino acid transporters and cholesterol biosynthetic enzymes. The amino acid transporter SLC7A5 is markedly upregulated following LPS stimulation, and conditional deletion of Slc7a5 impairs B cell proliferation, underscoring its essential role in B cell activation. LPS also elevates intracellular cholesterol levels, and inhibition of the rate-limiting enzyme HMG-CoA reductase blocks proliferation. This effect was mediated by a dual requirement for cholesterol metabolism and protein prenylation downstream of HMG-CoA reductase. Notably, this was not unique to TLR4 signalling but is also observed in B cells activated via TLR7, TLR9, CD40, or the B cell receptor. Together, these findings reveal that metabolic rewiring, including amino acid uptake and cholesterol metabolism, is an essential feature of B cell activation and proliferation.
    Keywords:  B cell; cholesterol; immunology; inflammation; mouse; statin; toll-like receptor
    DOI:  https://doi.org/10.7554/eLife.109093
  53. Curr Biol. 2026 May 18. pii: S0960-9822(26)00386-6. [Epub ahead of print]36(10): R450-R463
    Multinucleation as a recurring evolutionary strategy for scaling and plasticity.
    Gautam Dey, Markus Ganter, Marie Jacobovitz.
      Multinucleate cells - single cells containing multiple nuclei in a shared cytoplasm - are found across the eukaryotic tree of life. Having evolved independently in fungi, plants, protists, and animals, they thrive in environments ranging from nutrient-poor deep-sea sediments to dynamic soil microhabitats and host tissues. Multinucleate organization enables spatial specialization without internal partitions and facilitates rapid scaling of metabolic or transcriptional capacity, allowing organisms to forage across patchy resources, withstand physical stress, and respond quickly to environmental fluctuations. Yet multinucleation also brings challenges, including diffusion limits, the need for nuclear coordination, and the potential for genetic conflict. Its repeated emergence, often in lineages that have also evolved multicellularity, points to shared cellular, structural, and regulatory prerequisites shaped by ecological pressures. Here, we integrate perspectives from cell biology, ecology, and evolution to demonstrate that multinucleation is not a rare anomaly but a fundamental organizational strategy. Recognizing these systems as adaptive responses to environmental constraints provides a framework for uncovering general principles of cellular organization, evolution of life-cycle strategies, and the diversification of complex life.
    DOI:  https://doi.org/10.1016/j.cub.2026.03.066
  54. EMBO J. 2026 May 22.
    Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.
    Pooja Jadiya, Elena Berezhnaya, Devin W Kolmetzky, Dhanendra Tomar, Henry M Cohen, Shatakshi Shukla, Manfred Thomas, Salman Khaledi, Joanne F Garbincius, Liam Kennedy, Oniel Salik, Darpan Raghav, Alycia N Hildebrand, John W Elrod.
      Loss of mCa2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mitochondrial Ca2+ (mCa2+) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of mCa2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal mCa2+ uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca2+ content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu. These results suggest that inhibition of neuronal mCa2+ uptake represents a powerful therapeutic target to impede AD progression.
    DOI:  https://doi.org/10.1038/s44318-026-00809-w
  55. Annu Rev Cell Dev Biol. 2026 May 19.
    Beyond Kleiber's Law: Variation and Mechanisms of Metabolic Scaling.
    Liliana Piñeros, Rebecca Heald.
      The scaling relationship between metabolic rate and body mass is a foundational principle in biology that links physiology, ecology, and evolution. From early empirical studies-most notably Kleiber's observation of 3/4 power law scaling-to contemporary theoretical frameworks, decades of research have sought to explain why organismal metabolic rate increases more slowly than body mass. This review examines variation in scaling exponents across the tree of life and explores how cellular features, including cell size, mitochondrial dynamics, and energy storage, shape whole-organism metabolism. We describe how dynamic metabolic rates during embryonic development reveal patterns of energy use during growth, while deviations in metabolic scaling across species and disease states indicate how biological systems balance energy constraints with adaptive flexibility. Together, these insights position cells as the critical interface linking molecular bioenergetics to organismal function, evolution, and ecology.
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-015244
  56. Nat Genet. 2026 May 18.
    H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.
    Brian Krug, Bo Hu, Haifen Chen, Claudia Negrón-Lomas, Xiao Chen, Ahmed El Mouatani, Kristjan H Gretarsson, Adam Ptack, Shriya Deshmukh, Nisha Kabir, Wajih Jawhar, Augusto Faria Andrade, Elias Jabbour, Ashot S Harutyunyan, Xinrui Wang, Robert Taylor, John J Y Lee, Maud Hulswit, Damien Faury, Caterina Russo, Xinjing Xu, Jiahan Yang, Audrey Baguette, Nathan A Dahl, Alexander G Weil, Benjamin Ellezam, Rola Dali, Mathieu Blanchette, Khadija Wilson, Benjamin A Garcia, Rajesh Kumar Soni, Marco Gallo, Michael D Taylor, Claudia L Kleinman, Jacek Majewski, Nada Jabado, Chao Lu.
      Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range three-dimensional interactions, many of which resolve during lineage differentiation. Here we report that Polycomb-anchored looping is controlled by H3K27me3 spreading and regulates target gene silencing to influence cell fate specification. Using glioma-derived H3 Lys27-to-Met (H3K27M) mutations as tools to restrict H3K27me3 spreading, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened three-dimensional interactions that mirror the chromatin architecture of pluripotency. Conversely, H3K27me3 spread in pluripotent stem cells dilutes local cPRC1 chromatin concentration, weakening Polycomb loop contact frequencies. Disruption of cPRC1 binding or aggregation compromises stringent repression of Polycomb genes and induces differentiation and tumor regression of H3K27M-mutant glioma. These results identify the regulatory principles and disease implications of Polycomb looping and show that histone-modification-guided distribution of reader complexes is an important mechanism for nuclear compartment organization.
    DOI:  https://doi.org/10.1038/s41588-026-02586-y
  57. Redox Biol. 2026 May 15. pii: S2213-2317(26)00211-9. [Epub ahead of print]94 104213
    Nrf2 modulates cytosolic and mitochondrial calcium signal.
    Alessandra Preziuso, Artyom Y Baev, Fozila R Rustamova, Sharadha Dayalan Naidu, Lauren Millichap, Plamena R Angelova, Vincenzo Lariccia, Albena T Dinkova-Kostova, Andrey Y Abramov.
      Nrf2 is a transcription factor which regulates ∼1% of the mammalian genome and is responsible for orchestrating the cellular defense against oxidative, inflammatory and metabolic stress. Calcium (Ca2+) is a ubiquitous intracellular messenger which controls most cellular processes, from fertilization to cell death. Nrf2 and Ca2+ are involved in a large number of similar physiological processes, but it is not clear if they can regulate each other. Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.
    Keywords:  Astrocyte; Calcium signal; Keap1; Mitochondria; Neuron; Nrf2
    DOI:  https://doi.org/10.1016/j.redox.2026.104213
  58. Nat Immunol. 2026 May 18.
    Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation.
    Martina Kerndl, Laszlo Musiejovsky, Andrea Komljenovic, Hon Shing Lam, Andrea Vogel, Tobias Bausbacher, Christian J Riedl, Roko Sango, Lenka Matejovicova, Anja Dobrijevic, Laura Oberbichler, Melanie Hofmann, Markus Kieler, Lucia Quemada Garrido, Lara Veronika Perko Budja, Julia Stefanie Brunner, James Lucas Cairns, Paul Cheng, Kerstin Kitt, Christine Isaguirre, Thomas Köcher, Kristaps Klavins, Thomas Rattei, Simon Hametner, Stephan Blüml, Carsten Hopf, Ryan D Sheldon, Omar Sharif, Gernot Schabbauer.
      Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains unclear. Here, using a mouse neuroinflammation model coupled with genetic fate mapping, metabolomics and metabolite imaging, we identify that central nervous system (CNS) Mdc infiltration is associated with substantial metabolic changes and assign disease-linked metabolites therein. In particular, we found that increased arginine catabolism driven by lesion-associated arginase 1 (Arg1)-expressing Mdcs promoted oxidative damage, lipid accumulation and Mdc dysfunction. Genetic ARG1 deficiency within Mdcs during neuroinflammation increased extracellular arginine and was associated with rewiring of the CNS metabolic landscape, including attenuated disease-linked metabolites. This was accompanied by enhanced Mdc-driven anti-inflammation, regulatory T cell expansion and improved disease outcome. Opposing effects were observed following dietary arginine deficiency. Together, our work highlights key roles for Mdcs in CNS metabolism and reveals the pleiotropic beneficial effects of arginine in neuroinflammation.
    DOI:  https://doi.org/10.1038/s41590-026-02516-4
  59. EMBO J. 2026 May 21.
    Skin aging: mechanisms, evaluation, and rejuvenation.
    Runhan Li, Jingyun Zhang, Kehang Mao, Dawei Meng, Jing-Dong J Han.
      Skin aging, the most visible and accessible manifestation of organismal aging, reflects systemic physiological decline, compromising barrier integrity, immune defense, and regenerative capacity-functions essential for overall tissue homeostasis and longevity. Understanding why and how the skin ages offers crucial insights into tissue homeostasis and systemic aging. Here, we dissect the multi-layered mechanisms of skin aging across the epidermis, dermis, and appendages, highlighting how intrinsic cellular senescence, disrupted inter-compartmental communication, and dysregulation of the skin microbiome and hormonal signaling collectively undermine epithelial structure and function. We also summarize advances in quantitative evaluation of skin aging, from molecular signatures to morphological, microbial, and phenotypic indices, enabling objective assessment of biological age and intervention efficacy. Finally, we highlight rejuvenation strategies, encompassing rewiring of gene expression programs, metabolic modulation, microenvironmental remodeling, microbiome modulation, and hormone regulation, offering a framework for precision interventions and next-generation regenerative therapies.
    DOI:  https://doi.org/10.1038/s44318-026-00810-3
  60. bioRxiv. 2026 May 05. pii: 2026.05.01.718031. [Epub ahead of print]
    Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
    Praveen Kumar Guttula, Ganesan Muthusamy, Chin-Chi Liu, Priscilla Devora, Emi Sasaki, Tyler Butsch, Hasand Gandhi, James Moran, Manas Ranjan Gartia, Andrea N Johnston.
      The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the complex transition from hepatic steatosis to hepatocellular carcinoma. PGAM5 is a serine/threonine/histidine phosphatase that plays a role in mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Increased expression of PGAM5 in hepatocellular carcinoma is correlated with reduced patient survival. In this study, we demonstrate that loss of PGAM5 alters the bioenergetic landscape of liver cancer by promoting mitochondrial oxidant injury and suppressing the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion downregulates fatty acid biosynthesis, resulting in reduced cellular diacylglycerol concentrations through two probable mechanisms: attenuated long chain fatty acid uptake and suppressed de novo synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 to disrupt lipid metabolism in hepatocellular carcinoma.
    DOI:  https://doi.org/10.64898/2026.05.01.718031
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