bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–04–12
fifty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.
  2. PHGDH is a targetable driver of PDAC progression.
  3. Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
  4. Ferroptosis as an approach to leverage cancer metabolism.
  5. Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
  6. A feedback loop between cell proliferation and ROS regulates ferroptosis sensitivity.
  7. Drowning in cysteine.
  8. Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
  9. Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
  10. Metabolomics across scales: from single cells to population studies.
  11. Natural and Synthetic Metabolic Architectures.
  12. Mapping the mammalian dark metabolome by in vivo isotope tracing.
  13. LIFe of the sugar-free party in cancer metabolism.
  14. PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers.
  15. The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
  16. A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
  17. Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome.
  18. Stem cell function in vivo is supported by an alternative glycolysis endpoint.
  19. Toward actionable interventions in human aging (12th ARDD meeting, 2025).
  20. Mitochondrial Transfer: From Bench to Bedside.
  21. How to train your rodent: Recommendations for the preclinical study of exercise-induced benefits in metabolic research.
  22. Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.
  23. Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors.
  24. iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.
  25. Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
  26. Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
  27. Rethinking Mitochondria: The Extracellular Dimension.
  28. Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy.
  29. Fatty acid scavenging enables cancer escape from KRAS inhibition.
  30. Neutral lipid quality control gates ferroptotic cell death.
  31. Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.
  32. Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression.
  33. Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
  34. Global analysis of cancer cell responses to USP9X inhibition.
  35. Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.
  36. Targeting mitochondrial dynamics against cancer.
  37. Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.
  38. Diffusive spreading across dynamic mitochondrial network architectures.
  39. Organelle contact sites in cancer cells.
  40. Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.
  41. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  42. Inhibition of Acid Sphingomyelinase Links Sphingolipid Remodeling to Necroptotic Cell Death.
  43. Fat bursts T cells to drive joint inflammation.
  44. Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
  45. Mechanisms of human mitochondrial leaderless mRNA translation initiation.
  46. Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.
  47. Dissecting Complex Interactions Between Ferroptosis and the Proteasome.
  48. Repulsion from slow-diffusing nutrients improves microbial chemotaxis towards moving sources.
  49. SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth.
  50. Loss of Tumor-Infiltrating Lymphocytes and Poor Response to Immunotherapy in IDH GOF Mutant Melanoma.
  51. Exercise induces sex-specific assembly of mitochondrial supercomplexes.
  52. Ferroptosis as a therapeutic vulnerability in ARID1A-deficient bladder cancer.
  53. Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
  54. Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration.
  55. Uncovering cancer dependencies in peptide-interacting protein pockets.
  1. Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00192-9. [Epub ahead of print]
    Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.
    Chao Qin, Zhenhao An, Shu Feng, Wen Fu, Xinchi Xie, Ali Can Savas, Taolin Xie, Charles Brenner, Takeshi Saito, Pinghui Feng.
      Rapid cancer cell proliferation requires extensive macromolecular biosynthesis, yet how distinct anabolic pathways are coordinated remains incompletely understood. Here, we report that the trifunctional carbamoyl-phosphate synthase, aspartate transcarbamoylase, and dihydroorotase (CAD) activates key glycolytic enzymes to support biosynthesis and cancer cell proliferation. When cancer proteomics datasets were queried, a CAD activation signature was identified in diverse tumors. Metabolomics analysis revealed that CAD fuels central carbon metabolism, specifically the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP). Mechanistically, CAD deamidates and activates glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzymes of the PPP and SSP, respectively, which are fully recapitulated by the glutaminase domain of CAD. Functional interrogation of cancer-associated CAD mutations and human hepatocellular carcinoma tumors predicts the metabolic signature endowed by G6PD and PHGDH deamidation. Simultaneous inhibition of G6PD and PHGDH effectively impeded tumor formation. This work identifies CAD as a central carbon metabolism signaling node and a potential therapeutic target.
    Keywords:  CAD; Cancer metabolism; G6PD; PHGDH; central carbon metabolism; deamidation; pyrimidine synthesis; the pentose phosphate pathway; the serine synthesis pathway
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.016
  2. bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]
    PHGDH is a targetable driver of PDAC progression.
    Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.
      Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
    Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.
    DOI:  https://doi.org/10.64898/2026.03.11.711147
  3. Nat Metab. 2026 Apr 07.
    Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
    Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.
      Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.
    DOI:  https://doi.org/10.1038/s42255-026-01499-8
  4. Trends Cell Biol. 2026 Apr 09. pii: S0962-8924(26)00039-5. [Epub ahead of print]
    Ferroptosis as an approach to leverage cancer metabolism.
    Jenny Jin, Jiachen Hu, Mingyue Li, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Ferroptosis is a cell death process defined by the iron-mediated peroxidation of membrane phospholipids that overwhelms the cell's innate antioxidant capabilities. Sitting at the nexus of iron, lipid, reactive oxygen species stress responses, and cellular metabolism, ferroptosis is intricately tied to these pathways. The burgeoning field of cancer metabolism has revealed that cancer cells exhibit changes in ferroptosis-relevant metabolic pathways, thereby opening an important avenue of investigation into whether tumors can have characteristic metabolic alterations that render them exquisitely sensitive to ferroptotic cell death. In this review, we highlight recent findings in the metabolic pathways linking ferroptosis and oncogenesis, as well as implications for future cancer therapeutic strategies.
    Keywords:  cancer metabolism; ferroptosis; lipid metabolism; lipidomics; metabolomics; oncogenic signaling
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.008
  5. Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488
    Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
    Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.
      Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.
    Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite
    DOI:  https://doi.org/10.1016/j.canlet.2026.218488
  6. Front Cell Dev Biol. 2026 ;14 1756238
    A feedback loop between cell proliferation and ROS regulates ferroptosis sensitivity.
    Eric Seidel, E Yaren Itak, Fabienne Müller, F Isil Yapici, Johannes Brägelmann, Johannes Berg, Silvia von Karstedt.
       Background: Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and membrane rupture. While cellular populations reaching confluence are known to have limited sensitivity to ferroptosis, an understanding of the interplay between growth dynamics, reactive oxygen species (ROS) levels, metabolism and ferroptosis is currently lacking. This study aimed to establish a regulatory framework for the systemic interplay of these biological processes.
    Results: Here we use live-cell imaging coupled to ROS tracing to reveal a feedback loop between population growth and ferroptotic cell death. Starting out from the observation that the cellular proliferation rate declines with increased cellular density, we find that ROS levels also decline with increasing cellular density. In turn, low ROS levels make cells insensitive to ferroptosis, which enables population growth. Conversely, keeping cell numbers and drug concentration/cell constant while restricting growth space led to reduced proliferation, reduced ROS and decreased ferroptotic cell death. We find that this feedback between population growth and ferroptotic cell death leads to two steady states: (i) a ferroptosis-insensitive state characterized by slow growth, low levels of ROS and low rates of cell death and (ii) a ferroptosis-sensitive state characterized by rapid growth, ROS accumulation, and high rates of ferroptosis. A mathematical model of the feedback mechanism predicts the long-term fate of populations as well as their ferroptosis sensitivity when external conditions impacting cell proliferation rates, ROS, or both are changed. We tested the proposed feedback mechanism experimentally by interfering with lipid hydroperoxide clearance and by increasing cellular and lipid ROS production through a galactose-promoted OXPHOS switch.
    Conclusion: We find a feedback loop between population growth and ferroptotic cell death that dictates cellular fate (growth or cell death via ferroptosis) and is mechanistically determined by the levels of metabolic ROS. These results provide a unifying framework that dynamically links population growth and metabolic ROS regulation with ferroptosis sensitivity.
    Keywords:  ROS; feeedback loop; ferroptosis; lipid ROS; modelling
    DOI:  https://doi.org/10.3389/fcell.2026.1756238
  7. Nat Metab. 2026 Apr 07.
    Drowning in cysteine.
    Alec J Vaughan, Thales Papagiannakopoulos.
      
    DOI:  https://doi.org/10.1038/s42255-026-01511-1
  8. bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]
    Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
    Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.
      Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.
    DOI:  https://doi.org/10.64898/2026.03.29.715103
  9. Nat Metab. 2026 Apr 10.
    Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
    Tomas Paulenda, Maxim N Artyomov.
      
    DOI:  https://doi.org/10.1038/s42255-026-01493-0
  10. Nature. 2026 04;652(8109): 313-320
    Metabolomics across scales: from single cells to population studies.
    Theodore Alexandrov, Nicola Zamboni.
      Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.
    DOI:  https://doi.org/10.1038/s41586-026-10277-1
  11. Chembiochem. 2026 Apr 14. 27(7): e70302
    Natural and Synthetic Metabolic Architectures.
    Pablo I Nikel.
      Metabolic engineering often treats microbial metabolism as an inventory of metabolites, reactions, and the enzymes that catalyze them. This Perspective argues that function emerges from metabolic architecture, the connectivities that bind reactions into stable regimes shaped, among other factors, by space and time. The Japanese Metabolism movement motivates an architectural view in which the same metabolites could lead to rather different phenotypes when cells reconfigure metabolic routing subjected to environmental constraints. Natural examples, including the native cyclic glycolytic wiring of Pseudomonas putida, show how redox supply and carbon flow depend on regime-level organization and space-influenced state changes. The same principles explain why microbial engineering often fails when intermediates leak, cofactors are misallocated, or timing breaks productive hand-offs. Serine-based synthetic cycles for one-carbon assimilation expose these limits as they must couple carbon entry, redox demand, and amino acid pool control around a chiral metabolite linked to translation. The emerging picture is that future designs should make routing, insulation, compartmentalization, and metabolic segregation explicit engineering targets.
    Keywords:  central carbon metabolism; metabolic engineering; rational design; synthetic biology; synthetic metabolism
    DOI:  https://doi.org/10.1002/cbic.70302
  12. bioRxiv. 2026 Apr 02. pii: 2026.03.31.713900. [Epub ahead of print]
    Mapping the mammalian dark metabolome by in vivo isotope tracing.
    Michael R MacArthur, Justine Raeber, Wenyun Lu, Hantao Qiang, Amelia V Schueppert, Lucas B Ayres, Ricardo A Cordova, Michael D Neinast, Edmundo Leiva, Vanha N Pham, Jenna E AbuSalim, Connor S R Jankowski, Laith Z Samarah, Asael Roichman, Christian G Peace, Daniil G Ivanov, Gianna L Renzo, Anna M Oschmann, Julien F Ayroles, Sarah J Mitchell, Xi Xing, Kellen Olszewski, Hahn Kim, Joshua D Rabinowitz, Michael A Skinnider.
      Despite decades of biochemical study, a comprehensive map of the mammalian metabolome remains elusive. Mass spectrometry-based metabolomics detects thousands of small molecule-associated signals in mammalian tissues, but it is currently unclear how many of these reflect products of endogenous metabolism. Here, we leverage systematic in vivo isotope tracing to infer the biosynthetic origins of unidentified metabolites. We administered 26 different isotopically labelled nutrients to mice, measured circulating and tissue metabolite labelling by mass spectrometry, and developed a statistical framework to infer the number of carbon atoms incorporated from each of these precursors into more than 4,000 putative metabolites. We show this information can be harnessed for biosynthesis-aware structure elucidation using a multimodal AI model that co-embeds isotopic labelling patterns with chemical structures. This approach revealed several previously unrecognized families of mammalian metabolites, including cysteine-derived alkylthiazolidines, dithioacetal mercapturic acid derivatives, short-chain N-acyltaurines, acylglycyltaurines, and N-oxidized taurines. It further uncovered a family of mevalonate-derived isoprenoid metabolites that includes 2,3-dihydrofarnesoic acid, which is markedly depleted in both mouse and human aging. Age-related depletion of these isoprenoids is driven by impaired coenzyme A synthesis. Our work establishes the biosynthetic precursors for thousands of unidentified metabolites and reveals multiple previously unrecognized branches of mammalian metabolism.
    DOI:  https://doi.org/10.64898/2026.03.31.713900
  13. Trends Endocrinol Metab. 2026 Apr 09. pii: S1043-2760(26)00071-8. [Epub ahead of print]
    LIFe of the sugar-free party in cancer metabolism.
    Khaled Tighanimine, Brendan D Manning.
      Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. demonstrated that glucose withdrawal promotes cancer cell secretion of the cytokine leukemia inhibitory factor (LIF), which exerts protumorigenic effects on the TME.
    Keywords:  LIF; N-glycosylation; PERK; glucose; lung cancer; metastasis
    DOI:  https://doi.org/10.1016/j.tem.2026.03.010
  14. Nat Commun. 2026 Apr 07. pii: 2877. [Epub ahead of print]17(1):
    PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers.
    Hayden A Malone, Jacquelyn A Myers, Emma G Gruss, Marc A Morgan, Jake D Friske, Tabitha C McCarty, John J Navarro, Sarah Robinson, Rebecca L Halliburton, Sandra J Kietlinska, Francisca N De Luna Vitorino, Baranda S Hansen, Shondra M Pruett-Miller, Benjamin A Garcia, Martine F Roussel, Janet F Partridge, Charles W M Roberts.
      SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.
    DOI:  https://doi.org/10.1038/s41467-026-70699-3
  15. Nat Commun. 2026 Apr 09.
    The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-71630-6
  16. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123
    A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
    Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.
    Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis
    DOI:  https://doi.org/10.1073/pnas.2535453123
  17. Immunity. 2026 Apr 08. pii: S1074-7613(26)00075-0. [Epub ahead of print]
    Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome.
    TRACERx Consortium
      DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.
    Keywords:  SMG1; cancer immunopeptidome; cancer immunotherapy; cryptic peptides; non-canonical neoantigens; nonsense-mediated mRNA decay; patient-derived fragments; tumor immunogenicity
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.005
  18. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715412. [Epub ahead of print]
    Stem cell function in vivo is supported by an alternative glycolysis endpoint.
    Edward O Kwarteng, Yafeng Li, Dieu Linh Nguyen, Michalis Agathocleous.
      Carbohydrates are classically catabolized by fermentation or oxidation, a choice that impacts many cellular functions including proliferation. Proliferating cells including somatic stem and progenitor cells are thought to favor fermentation over oxidation, and most proliferating cells in vitro depend on lactate production. However, it has not been tested if fermentation and oxidation are the universal obligatory terminal fates for carbohydrates in vivo because the key enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), have not been simultaneously deleted in any cell type. Here we show that both fermentation and oxidation are dispensable for the survival and function of hematopoietic stem cells (HSC). Combined LDHA and LDHB deletion to ablate LDH did not impair HSC function, suggesting that HSCs and rapidly proliferating hematopoietic progenitors surprisingly do not require fermentation. Combined LDHA, LDHB, and PDH deletion abolished both glucose oxidation and fermentation, but did not impair HSC function. Glycolysis was preserved, suggesting the operation of an alternative endpoint. LDH/PDH-deficient HSCs terminated glycolysis through pyruvate export. Pyruvate export by HSCs and progenitors was a physiological response to changing nutrient levels. Quadruple deletion of LDHA/B, PDH, and the pyruvate transporter MCT1 impaired HSC function. This suggested that an essential role of glycolysis termination is not to produce acetyl-CoA or lactate but to remove pyruvate. Therefore, in contrast to classical theories and to in vitro metabolism, carbohydrate metabolism in vivo does not require oxidation or fermentation but can terminate directly in pyruvate export, and this alternative pathway is sufficient to support stem cell function.
    DOI:  https://doi.org/10.64898/2026.03.30.715412
  19. Aging (Albany NY). 2026 Apr 06. 18(1): 282-302
    Toward actionable interventions in human aging (12th ARDD meeting, 2025).
    Aleksandr Dekan, Sierra Lore, Ye Eun Yoon, Aisyah Sjöholm, Alexander Tyshkovskiy, Alexey Terskikh, Ana Maria Cuervo, Anastasia Georgievskaya, Andrea Heinz, Andrei Seluanov, Andrew Adams, Andy P Tsai, Anna Murray, Anne Brunet, Anne Marije van Harten, Avi Spier, Ben Shenhar, Bente Klarlund Pedersen, Berthil Clasen, Björn Schumacher, Brian K Kennedy, Charlotte Suetta, Christiane Volbracht, Christoph Kuppe, Clive Cookson, Collin Y Ewald, Cristiana Banila, Daisy Cai, Dario Riccardo Valenzano, Dudley W Lamming, Edward Rudnic, Elias Bou Samra, Emma Teeling, Eric Verdin, Evandro Fei Fang, Fabrizio d'Adda di Fagagna, Fedor Galkin, Garri Zmudze, Heinrich Jasper, In Hwa Jang, Jing-Dong Jackie Han, Jamie Justice, Jan H J Hoeijmakers, Javier María Peralta Ramos, Jean-Marc Lemaitre, Jeroen Aerssens, Joe Betts-LaCroix, John C Newman, Juan Carlos Izpisua Belmonte, Kazuto Kawamura, Kennedy Matsagas Schaal, Kitsu Egerton, Kotb Abdelmohsen, Kristen Fortney, Lars Hartenstein, Laura Niedernhofer, Lida Katsimpardi, Lisa Melton, Lotte Bjerre Knudsen, Luigi Ferrucci, Lykke Sylow, Marco Demaria, Marissa J Schafer, Marta Guasch-Ferré, Martin Borch-Jensen, Maxim Kholin, Michael Antonov, Michael Levitt, Michela Deleidi, Miriam Merad, Morten Meldal, Mourad Topors, Murali Venkatesan, Nathan K LeBrasseur, Niklas Anzinger, Peter Fedichev, Paul Kohlhaas, Peter J Mullen, Priya Singhal, Rafael de Cabo, Riekelt H Houtkooper, Rusty Montgomery, Ryan Smith, Sharon Rosenzweig-Lipson, Sergey Jakimov, Steve Horvath, Steven Austad, Thomas A Rando, Todd White, Tom Zuber, Tomaz Rozmaric, Tony Wyss-Coray, Tuomas Tammela, Vadim N Gladyshev, Vanessa V C Sinatti, Weilan Wang, William Harborne, Xiaodong Liu, Xing Li Wang, Yousin Suh, Yuta Lee, Zane Koch, Alex Zhavoronkov, Morten Scheibye-Knudsen, Daniela Bakula.
      The 12th Aging Research and Drug Discovery (ARDD) meeting convened at the University of Copenhagen, presenting a comprehensive overview of recent advancements in the biology of aging. A central theme across sessions was the field's gradual shift from descriptive, correlational studies to mechanistic understandings enabling the engineering of personalized therapeutic interventions aimed at extending human healthspan. Key discussions highlighted the convergence of multiple disciplines. Presentations detailed how fundamental biological insights are being integrated with artificial intelligence and machine learning platforms for accelerated target identification and drug development. Furthermore, the development and application of novel preclinical research models were presented as critical for improving the translational pipeline to human clinical trials. Scientific discourse has advanced from cataloging the established hallmarks of aging to identifying and modulating the specific molecular mechanisms that regulate them. This focus is predicated on the hypothesis that aging is not solely a result of stochastic damage accumulation but may be a tractable, modifiable, and potentially reversible biological process amenable to intervention. This report summarizes the principal research directions and conceptual frameworks presented at the conference.
    Keywords:  aging; biomarkers; geroscience; longevity; rejuvenation
    DOI:  https://doi.org/10.18632/aging.206368
  20. Circ Res. 2026 Apr 10. 138(8): e326984
    Mitochondrial Transfer: From Bench to Bedside.
    Gentaro Ikeda, Jiwen Li, Alyssa Wang, Amogha Medha Paleru, Phillip C Yang.
      Intercellular mitochondrial transfer has emerged as a fundamental mechanism of tissue adaptation and repair in the cardiovascular system, with major implications for cardiovascular, neurological, metabolic, and inflammatory diseases. Once thought to be static, mitochondria are now recognized as mobile organelles that move between cells via tunneling nanotubes, extracellular vesicles, and free mitochondria. These pathways support 2 complementary axes of mitochondrial communication: Rescue by Replenish, in which healthy mitochondria or mitochondrial components restore bioenergetics and stress resistance in recipient cells, and Relief by Release, in which damaged mitochondria are exported for degradation to preserve homeostasis and limit inflammation. We summarize the molecular machinery governing tunneling nanotube formation, mitochondria-derived vesicle biogenesis, extracellular vesicle sorting, and free mitochondrial release and uptake, and discuss how these processes shape organ function. Building on these mechanistic insights, we outline 4 translational strategies: (1) cell-based therapies that donate healthy mitochondria or scavenge damaged ones; cell-free approaches using (2) mitochondria-containing extracellular vesicles or (3) purified mitochondria; (4) pharmacological, nutritional, and lifestyle interventions that augment endogenous mitochondrial turnover and intercellular exchange. Finally, we discuss key barriers to clinical translation, including inflammatory and oncogenic risks, mitonuclear incompatibility, incomplete understanding of the fate and durability of transferred mitochondria, and the lack of standardized manufacturing, potency assays, and long-term storage methods. Continued integration of mechanistic biology with bioengineering and regulatory science will be essential to safely move mitochondrial transfer-based therapies from bench to bedside in cardiovascular medicine.
    Keywords:  cell communication; energy metabolism; extracellular vesicles; homeostasis; inflammation; mitochondria; nanotubes
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326984
  21. Cell Metab. 2026 Apr 06. pii: S1550-4131(26)00099-9. [Epub ahead of print]
    How to train your rodent: Recommendations for the preclinical study of exercise-induced benefits in metabolic research.
    Steffen H Raun, Tang Cam Phung Pham, Mark R Viggars, Satoru Ato, Yuta Takagaki, Zhen Yan, Katrien De Bock, Troy A Hornberger, Erik A Richter, Johan Auwerx, Laurie J Goodyear, Mark A Febbraio, Karyn A Esser, Lykke Sylow.
      Regular physical activity is fundamental in promoting health and longevity. Numerous studies highlight the beneficial effects of exercise on metabolic parameters, but uncovering the mechanisms underlying the complex cellular responses and adaptations remains challenging in humans. Thus, animal models, in particular rodent models, have been indispensable for unveiling the underlying biological responses to exercise. Studies with precise exercise designs and diverse genetic models are vital for uncovering mechanistic pathways and informing pharmacological and behavioral strategies to combat non-communicable chronic diseases. Despite decades of research, recommendations to design preclinical exercise interventions and to measure key metabolic exercise adaptations in rodents have yet to be established. To enhance animal-to-human translation and ensure reproducibility, exercise studies must be rigorously controlled. Here, we outline key experimental considerations in rodents, including protocol design, exercise modality, sex, age, housing temperature, and circadian rhythm, to guide best practices and promote standardization and translation in future preclinical exercise studies.
    Keywords:  adipose tissue; exercise; hypertrophy; metabolism; mouse; muscle; training
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.005
  22. Trends Cancer. 2026 Apr 09. pii: S2405-8033(26)00057-9. [Epub ahead of print]
    Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.
    Chloe Slater, Albane Simon, Marguerite Laprie-Sentenac, Laurie Menger.
      T cell exhaustion is an adaptive dysfunctional state driven by chronic antigen exposure and an immunosuppressive tumor microenvironment, which significantly impedes effective antitumor immunity and T cell therapies. This progressive loss of effector function and memory potential is governed by the complex and coordinated interplay of epigenetic, transcriptional, epitranscriptomic, and metabolic networks, which collectively establish stable exhaustion-associated programs. Emerging evidence demonstrates that modulating these layers, whether permanently or transiently, can reverse exhaustion and reinvigorate T cell function. Furthermore, core metabolites serve as shared cofactors, directly linking cellular metabolism to these epigenetic and epitranscriptomic changes. Characterizing these multilayered regulatory mechanisms is critical for developing novel strategies to reprogram exhausted T cells and improve therapeutic efficacy against cancer.
    Keywords:  CAR T cells; T cell exhaustion; T cell therapy; epigenetics; epitranscriptomics; metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.002
  23. Sci Immunol. 2026 Apr 10. 11(118): eadx4411
    Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors.
    Chenyu Zhang, Charles Chien, Eglė Jurgaitytė, Koharu Sakiyama, Alissa Bockman, Yeara Jo, Seungwon Lee, Stephanie Silveria, Elizabeth Andrews, Abigail Mende, Lily Zhang, K Christopher Garcia, Allon Wagner, Michel DuPage, David Raulet.
      Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (Treg cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I+ cancers that expressed NKG2D ligands. Treg cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-Treg cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-Treg cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of Treg cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of Treg cells in tumors can control CD8 T cell-resistant cancers.
    DOI:  https://doi.org/10.1126/sciimmunol.adx4411
  24. Nat Metab. 2026 Apr 10.
    iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.
    Marina Diotallevi, Carlos Outeiral, Priyanka Patel, Gareth S D Purvis, Surawee Chuaiphichai, Thomas Nicol, Faseeha Ayaz, Daniel A Nissley, Ganna O Krasnoselska, Svenja Hester, John H McVey, Roman Fischer, Benedikt Kessler, Charlotte M Deane, Raymond J Owens, Keith M Channon, Mark J Crabtree.
      Nitric oxide (NO) has fundamental roles in numerous physiological and pathophysiological processes. In macrophages, NO produced by inducible nitric oxide synthase (iNOS) modulates metabolic changes that are essential to macrophage activation and plasticity, driving the characteristic metabolic switch from oxidative phosphorylation to glycolysis1,2. Itaconate, derived from the TCA cycle by decarboxylation of cis-aconitate by IRG1 (also referred to as CAD, ACOD1), is one of the most upregulated metabolites during the inflammatory response3. Itaconate regulates macrophage polarization by electrophilically modifying cysteines of key enzymes that control inflammatory states (such as ATF3, Jak1, IFNβ), participate in glycolysis (for example, GAPDH, LDHA) and limit oxidative stress through structural competitive inhibition of succinate dehydrogenase4-9. We recently reported that macrophages that are deficient in iNOS, and subsequent NO generation, produce strikingly higher levels of intracellular itaconate (up to ~15-fold) compared to wild-type cells when stimulated with inflammatory cytokines1,2,10. Here we show that iNOS inhibits IRG1 activity and itaconate levels through a conformation-dependent protein-protein interaction rather than through the production of NO. Using a variety of biochemical and computational approaches, we show that a direct interaction between iNOS and IRG1 occurs within mitochondria, in mouse and human cells, and that it depends on binding of the cofactor BH4 to iNOS but does not require its capability to produce NO. Our findings reveal a non-canonical cellular function for iNOS that places it at the centre of a signalling hub, linking redox signalling and metabolism to modulation of the inflammatory response in macrophages.
    DOI:  https://doi.org/10.1038/s42255-026-01492-1
  25. Cancer Metab. 2026 Apr 04.
    Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
    Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Matthew D Perricone, Heather Giza, Peter Sajjakulnukit, Amy L Myers, Zeribe C Nwosu, Jonathan M Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis.
      
    DOI:  https://doi.org/10.1186/s40170-026-00428-3
  26. Cell. 2026 Apr 03. pii: S0092-8674(26)00272-2. [Epub ahead of print]
    Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
    Clemens Hinterleitner, Hailey V Goldberg, Domhnall McHugh, Valentin J A Barthet, Aveline Filliol, Scott W Lowe.
      Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.005
  27. Circ Res. 2026 Apr 10. 138(8): e326988
    Rethinking Mitochondria: The Extracellular Dimension.
    Laura Pena-Couso, Magdalena Makuch, Jose Angel Nicolas-Avila.
      Mitochondria are essential organelles that transform the energy contained in metabolic substrates into ATP while supporting numerous cellular processes. Traditionally regarded as strictly intracellular, growing evidence now demonstrates that mitochondria and mitochondria-derived components can also be released into the extracellular space, giving rise to extracellular mitochondria. extracellular mitochondria display remarkable heterogeneity, ranging from intact organelles to individual molecular components, free to vesicle-encapsulated structures, and with functional states spanning from severely damaged to metabolically active. Their release is mediated by tightly regulated mechanisms in both living and dying cells, and is influenced by cellular stress, activation state, and pathways that control mitochondrial selection, compartmentalization, trafficking, and extrusion. Extracellular release fulfills multiple functions across the organism, including quality control, modulation of cellular identity, inflammatory signaling, and functional support of recipient cells. In the cardiovascular system, extracellular mitochondria contribute to both homeostasis and disease progression. This review summarizes current knowledge of extracellular mitochondria forms, mechanisms of release, and pathophysiological relevance, and highlights their emerging potential as therapeutic targets in cardiovascular pathophysiology and beyond.
    Keywords:  cardiovascular system; extracellular space; homeostasis; mitochondria; organelles
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326988
  28. Trends Immunol. 2026 Apr 09. pii: S1471-4906(26)00069-4. [Epub ahead of print]
    Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy.
    Xin Chen.
      Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has attracted considerable attention in tumor biology and cancer therapy. Beyond its intrinsic role in tumor suppression, ferroptosis greatly influences the tumor immune microenvironment. Ferroptotic tumor cells release damage-associated molecular patterns, oxidized lipid mediators, and nucleic acids, which can either activate or suppress antitumor immunity. Conversely, immune cells modulate tumor cell sensitivity to ferroptosis through the secretion of cytokines and metabolites. In this review, we summarize the current understanding of the interplay between ferroptosis and tumor immunity. Targeting ferroptosis may offer broad opportunities to enhance tumor immunotherapy.
    Keywords:  ferroptosis; immune evasion; immunoferroptosis; immunotherapy; tumor immunity
    DOI:  https://doi.org/10.1016/j.it.2026.03.008
  29. bioRxiv. 2026 Apr 03. pii: 2026.04.01.715565. [Epub ahead of print]
    Fatty acid scavenging enables cancer escape from KRAS inhibition.
    Zihang Yuan, Bo Lin, Chunlan Wang, Yingying Miao, Da Zhang, Ziru Meng, Gangqi Wang, Andrew M Lowy, Michael Karin, Fei Yang, Beicheng Sun, Hua Su.
      Although inhibitors of oncogenic KRAS have shown clinical efficacy 1 , resistance to KRAS inhibition is common 2 , and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3Kα signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3Kγ-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3Kγ signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.
    DOI:  https://doi.org/10.64898/2026.04.01.715565
  30. Trends Cell Biol. 2026 Apr 08. pii: S0962-8924(26)00042-5. [Epub ahead of print]
    Neutral lipid quality control gates ferroptotic cell death.
    Hui Zhang, Xiaojun Cai, Quazi T H Shubhra.
      By uncovering a lipid droplet (LD) quality-control pathway driven by ferroptosis suppressor protein 1, Lange et al. show that neutral-lipid oxidation shapes ferroptosis vulnerability. This work expands ferroptosis regulation beyond membrane phospholipids and positions LDs as active redox control sites with broad implications for cell fate regulation.
    Keywords:  Cell death regulation; Ferroptosis; Lipid droplets; Neutral lipid metabolism; Organelle-specific redox control
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.011
  31. Nat Aging. 2026 Apr 06.
    Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.
    Huilong Li, Ruzhou Zhao, Luming Wan, Yang Yuan, Enhao Ma, Yingang Li, Zhuangzhuang Chen, Binbin Liu, Yurong Song, Ziwei Cao, Xinxin Jiao, Yue Wang, Peng Wu, Hao Jin, Jiatong Li, Xiaopan Yang, Linfei Huang, Yanhong Zhang, Ke Yang, Jiang Huo, Haoran Jin, Hui Zhong, Min Min, Shaohua Zhang, Yuan Cao, Wenlong Li, Rui Zhang, Congwen Wei.
      Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes PTEN and LATS2, as well as enhanced epithelial-mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.
    DOI:  https://doi.org/10.1038/s43587-026-01102-5
  32. Cell Chem Biol. 2026 Apr 07. pii: S2451-9456(26)00105-4. [Epub ahead of print]
    Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression.
    Chengheng Liao, Siying Lyu, Rebecca L Johnson, Tiantian Shang, Xiaoyu Wang, Nina Gildor, Shina Li, Noelle S Williams, Lindsey I James, Lianxin Hu, Qing Zhang.
      Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, often features the inactivation of the von Hippel-Lindau (VHL) tumor suppressor, creating therapeutic vulnerabilities. Although HIF2α inhibitors have shown clinical promise, many VHL-deficient tumors remain resistant. -binding kinase 1 (TBK1) has emerged as a synthetic lethal target in this context. Here, we report UNC8209, an optimized cereblon(CRBN)-recruiting proteolysis-targeting chimera (PROTAC) that selectively and potently degrades TBK1. Compared with earlier TBK1 degraders, UNC8209 exhibits enhanced degradation efficiency and improved selectivity over off-target kinases, including IKKε. TBK1 degradation by UNC8209 suppresses proliferation in VHL-deficient ccRCC models and impairs tumor growth in vivo with minimal toxicity within a defined therapeutic window. In addition, the anti-proliferative effects of UNC8209 extend to multiple tumor types addicted to elevated TBK1 activity. Together, these findings establish UNC8209 as a selective chemical probe and support TBK1 degradation as a therapeutic strategy in TBK1-dependent cancers.
    Keywords:  PROTAC; TBK1; VHL; cancer therapeutics; ccRCC; cereblon; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.013
  33. Circ Res. 2026 Apr 10. 138(8): e326982
    Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.
    Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
  34. EMBO J. 2026 Apr 07.
    Global analysis of cancer cell responses to USP9X inhibition.
    Philipp Schenk, Shane M Devine, Simon A Cobbold, Niall D Geoghegan, Elizabeth L Kyran, Ching-Seng Ang, Jack A Alexandrovics, Dale J Calleja, Dylan H Multari, Vineet Vaibhav, Bernadine G C Lu, Theresa A Klemm, Laura F Dagley, Kym N Lowes, Nicholas A Williamson, Pieter J A Eichhorn, Ashley P Ng, Rebecca Feltham, David Komander.
      The ubiquitin-specific protease (USP) USP9X is a human deubiquitinase (DUB) with a large number of described targets and cellular roles. In cancer, USP9X is found as an oncogene or as a tumour suppressor depending on context, and its utility as a target for cancer therapy remains unclear. We here describe WEHI-092, a piperazine-based USP9X-specific small-molecule inhibitor, which binds to a unique region in the USP9X Fingers-subdomain, distinct from known DUB-inhibitor binding sites. Using proteomics and ubiquitinomics, we show that USP9X targets distinct substrates compared to USP7, yet the substrate profile of USP9X varies significantly across cancer cell lines. We reveal a core set of 17 proteins commonly regulated by USP9X in most cell lines, which we consider as proximal biomarkers for USP9X inhibition. Consistent with proteomics, we show in unrelated cell lines that WEHI-092 treatment arrests the cell cycle in metaphase without inducing cell death. This explains growth suppression in long-term clonogenic assays in most cancer cell lines, and positions USP9X inhibitors as a new class of selective mitotic poisons.
    Keywords:  Cancer; DUB Inhibitor; Substrate Identification; USP9X; Ubiquitinomics
    DOI:  https://doi.org/10.1038/s44318-026-00742-y
  35. bioRxiv. 2026 Apr 03. pii: 2026.03.31.715681. [Epub ahead of print]
    Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.
    Oriana Y Teran Pumar, Elton L VanNoy, Abigail Haffey, Durga Prasad Gannamedi, Christine Isabelle Rafie, Dylan Scott Lykke Harwood, Julia R Benedetti, Christine Ann Pittman Ballard, Erika Ciervo, Pedro Henrique Assenza Tavares Coroa, Payal Grover, Brandon Emanuel León, Jonathan Mitchell, Asmita Pathak, Bruno Colon, Lyenne El Ghorayeb, Laura O'Sullivan, Venu Venkatarame Gowda Saralamma, Clara Lopez Ruiz, Natasha Khatwani, Surinder Kumar, Priyamvada Rai, Jonathan Schatz, Ashish Shah, Zev A Binder, Michele Ceccarelli, Quinn T Ostrom, Bjarne Winther Kristensen, Erietta Stelekati, Dionysios C Watson, David B Lombard, Dalia Haydar, Defne Bayik.
      Metabolic dysfunction is a hallmark of CD8 + T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8 + T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8 + T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8 + T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8 + T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8 + T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8 + T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8 + T cell responses.
    DOI:  https://doi.org/10.64898/2026.03.31.715681
  36. Trends Cell Biol. 2026 Apr 03. pii: S0962-8924(26)00037-1. [Epub ahead of print]
    Targeting mitochondrial dynamics against cancer.
    Yu-Lu Cao, Chao-Pin Yang, Birong Shen, Junjie Hu, Song Gao.
      Although cancer treatment has improved, many patients exhibit limited responses due to the intrinsic heterogeneity and adaptability of tumors, coupled with immunosuppressive conditions in the tumor microenvironment (TME). Mitochondrial dynamics, characterized by continuous fusion and fission, influences cellular processes such as metabolism, cell cycle, cell death, and stemness, thereby profoundly shaping tumor cell evolution and TME plasticity. In this review, we summarize recent advances regarding the roles of mitochondrial dynamics in cancer biology and discuss how it regulates the behavior of both tumor cells and tumor-associated immune cells in the TME. We propose that targeting mitochondrial dynamics represents a dual therapeutic strategy that disrupts core oncogenic programs while potentiating antitumor immunity, offering a promising direction for future cancer treatment.
    Keywords:  TME; immunotherapy; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.006
  37. Sci Rep. 2026 Apr 10.
    Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.
    Lidia de Bari, Mariano Francesco Caratozzolo, Giuseppe Petrosillo, Miriana Calò, Cinzia Antognelli, Tatiana Armeni, Andrea Scirè, Miklós Péter Kalapos.
      Although metformin (MET), the well-known antidiabetic drug, exhibits clear antineoplastic effects and is reported to target mitochondria, several issues are still open in this regard, thus limiting its utilization as an anticancer drug alone or in combination with other molecules. Here a functional investigation was carried out to reveal how MET impacted on mitochondrial functions and cell energy metabolism in human cultured clear cell renal carcinoma cells (ccRCCs), in which the anticancer effect of MET is already known. The in vitro effect of increasing MET concentrations on cell viability, necrosis and apoptosis of ccRCCs was checked and compared to normal immortalized HK2 cells. At the same time, the effect of MET on mitochondrial functions, ATP synthesis via oxidative phosphorylation, cellular ATP level, L-lactate (L-LAC) production and export, glucose consumption and key mitochondrial and cytosolic enzyme activities was also investigated in cancer cells. MET affected ccRCC viability and impaired mitochondrial respiration, membrane potential generation and ATP production by targeting complex I (CI), III and IV of the respiratory chain at a concentration near to the IC50 value (25 mM). Importantly, we first identified a significant inhibition of the adenine nucleotide translocator (ANT) activity in response to MET treatment. Notably, the sensitivity of ANT and CI activity to increasing MET concentrations differed markedly, the former being considerably inhibited already at a low, near-clinically relevant concentrations, while the latter only at concentrations ≥ 1 mM. The drug also induced a glycolytic shift in ccRCCs and increased the activity of the mitochondrial flavoenzymes succinate dehydrogenase (SDH) and D-lactate dehydrogenase (D-LDH), and of the key enzymes of the pay-off phase of glycolysis, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) and pyruvate kinase (PK). Nevertheless, cellular ATP level dropped markedly, and the intracellular L-LAC amount was almost doubled in the presence of MET. Interestingly, MET-induced glycolytic shift showed a drug concentration dependence similar to that seen for CI inhibition, suggesting not ANT but rather CI inhibition may be the trigger for metabolic rewiring. These findings give new insights into MET mechanisms of action which may potentially improve its application and outcome in cancer as well as in other pathologies.
    Keywords:  Adenine nucleotide translocator; Clear cell renal cell carcinoma; Glycolysis; Metformin; Mitochondrial respiratory chain complexes; Oxidative phosphorylation
    DOI:  https://doi.org/10.1038/s41598-026-48200-3
  38. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2523913123
    Diffusive spreading across dynamic mitochondrial network architectures.
    Keaton B Holt, Camryn Zurita, Lizzy Teryoshin, Samantha C Lewis, Elena F Koslover.
      In eukaryotic cells, mitochondria form networks that range from highly fused interconnected structures to fragmented populations of individual organelles that undergo transient interactions. These structures can be described as temporal networks of physical units, whose dynamic topology is determined by fusion, fission, and motion of the mitochondria through intracellular space. The heterogeneity of the mitochondrial population is governed by diffusive transport and interunit exchange of proteins, lipids, ions, and RNA within these networks. We present a unifying framework for the dispersion of material within temporal networks of spatially embedded units that span across a broad connectivity range. Specifically, we consider filling of the networks with a locally produced but globally consumed material, demonstrating that the steady-state content is determined by the balance of timescales for spatial encounter between clusters, local fusion, fission, and diffusive transport within a cluster. As the connectivity increases, filling behavior transitions from three-dimensional spread through a "social network" limited by cluster interactions to low-dimensional transport through a largely stationary "physical network" limited by material diffusivity. We extract parameters for mitochondrial networks in three human cell lines, demonstrating that different cells can access both the social and the physical network regimes. These results provide a quantitative basis for predicting the homogenization of biomolecules through a mitochondrial population. Our framework unifies a variety of temporal network structures into an overarching theory for transport through populations of interacting and interconnected units.
    Keywords:  intracellular transport; mitochondria; networks; organelle dynamics; temporal networks
    DOI:  https://doi.org/10.1073/pnas.2523913123
  39. Cell Death Dis. 2026 Apr 04.
    Organelle contact sites in cancer cells.
    Ilaria Celotti, Matteo Scavezzon, Sabrina Toffanin, Alessia Ruzza, Federica Vianello, Elisabetta Zaltron, Carol Bastianello, Michela Rossini, Filippo Severin, Luigi Leanza.
      Membrane contact sites (MCSs) are defined as regions of functional proximity between membranes belonging to the same or different organelle types. These interactions are mediated by specialised proteins promoting the formation of these crosstalk hubs. Previously, organelles were considered to act independently in cellular physiology. However, it is now evident they carry out specific functions at MCSs. The first interactions described involved endoplasmic reticulum and mitochondria. Subsequently, many contacts involving different organelles emerged. MCSs affect several cellular processes, including intracellular signalling, lipid and ion homeostasis, transport of molecules, cellular metabolism, and redox balance. Disruption of these interactions has been described to be associated with various pathologies, including cancer. While the role of MCSs in tumours remains unclear, recent findings suggest they may influence cancer progression, so, in the near future, modulating organelle interactions could provide novel therapeutic options and develop new protocol to treat tumours.Schematic overview of intracellular MCSs, their effects on biological processes and the associated cancer-related outcomes. MCSs involve different cellular organelles allowing their intercommunication, finally participating in a plethora of cellular processes ranking from calcium and ions exchange, lipid transport and regulation of cell survival. Thus, MCSs modulation has been demonstrated to play a pivotal role in the modulation of cancer aggressiveness.
    DOI:  https://doi.org/10.1038/s41419-026-08674-5
  40. Am J Physiol Gastrointest Liver Physiol. 2026 Apr 09.
    Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.
    Yuezhong Zhang, Yinzhi Ying, Wesley Huang, Zoe A Rosenfeld, Marwa O El-Derany, Zheng Hong Lee, Cristina Castillo, Tae Gyu Oh, Joel K Greenson, Yatrik M Shah.
      Broad antioxidant strategies in inflammatory bowel disease have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species (ROS). In our recent work, we demonstrated that fibroblast-specific overexpression of acyl-CoA synthetase long-chain family member 4 (ACSL4) reprogrammed lipid metabolism and sensitized adjacent epithelial cells to ferroptosis in IBD models, pointing to heterocellular lipid crosstalk as a driver of epithelial injury. Building on that insight, here we test the hypothesis that fibroblast glutathione peroxidase 4 (GPX4), a key enzyme detoxifying lipid hydroperoxides, is critical in restraining fibroblast-mediated lipid peroxidation and consequent epithelial ferroptosis during colitis. We generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice and subjected them to acute DSS colitis. Fibroblast-specific GPX4 deletion did not alter basal colon morphology but significantly aggravated DSS-induced injury. Increased histological scores, greater weight loss, and colon shortening versus littermate control mice. In vitro, GPX4-deficient fibroblasts exhibited elevated lipid peroxidation in response to ferroptosis inducers, reversible by liproxstatin-1. Critically, liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient animals, restoring colon length, weight loss, and histologic injury. Together, these findings identify fibroblast GPX4 as a gatekeeper that limits stromal lipid peroxidation and suppresses epithelial ferroptosis under inflammatory stress. Targeting fibroblast-mediated lipid peroxidation may offer a refined therapeutic axis in IBD.
    Keywords:  GPX4; inflammatory bowel disease; lipid peroxidation
    DOI:  https://doi.org/10.1152/ajpgi.00387.2025
  41. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  42. bioRxiv. 2026 Mar 12. pii: 2026.03.10.710852. [Epub ahead of print]
    Inhibition of Acid Sphingomyelinase Links Sphingolipid Remodeling to Necroptotic Cell Death.
    Luis Pilapil, Shweta Chitkara, G Ekin Atilla-Gokcumen.
      Necroptosis is a lytic form of programmed cell death that requires activation of the RIPK1/3- MLKL complex and results in plasma membrane permeabilization. Although the protein components governing necroptosis are well defined, the lipid determinants of this process remain poorly understood. Here, we combined lipidomics, pharmacological perturbations of sphingolipid metabolism and functional assays to identify sphingolipid pathways that contribute to necroptotic cell death. Using a panel of small molecule inhibitors, we found that inhibition of acid sphingomyelinase (ASMase) with ARC39 restored cell viability and membrane integrity during necroptosis without altering canonical necroptotic signaling. Lipidomic analysis revealed that ARC39 treatment prevented ceramide accumulation in necroptosis, linking reduced ceramide levels to decreased membrane permeability. Interestingly, ARC39 treatment did not reduce total cellular levels of phosphorylated MLKL (pMLKL) nor its initial membrane association, suggesting that the observed decrease in membrane permeability arises downstream of MLKL activation. Instead, our findings support a model in which the reduction of ceramide levels impairs productive membrane insertion and pore formation by pMLKL. Consistent with this interpretation, genetic knockdown of ASMase similarly resulted in increased cell viability, decreased membrane permeabilization, and decreased ceramide levels during necroptosis, further linking ceramide homeostasis to necroptotic membrane damage. Together, these results indicate that ASMase-derived ceramides are important for efficient MLKL-mediated membrane permeabilization in necroptosis.
    DOI:  https://doi.org/10.64898/2026.03.10.710852
  43. Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00050-1. [Epub ahead of print]38(4): 641-642
    Fat bursts T cells to drive joint inflammation.
    Wei Li, George C Tsokos.
      Chronic autoimmune inflammation is increasingly understood to be shaped by the tissue metabolic environment. Weyand and colleagues show that lipid-rich tissues trigger lipid droplet-dependent, gasdermin D-mediated pyroptosis in metabolically exhausted CD4+ T cells, thereby sustaining inflammatory pathology.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.007
  44. Circ Res. 2026 Apr 10. 138(8): e326986
    Intercellular Mitochondrial Transfer: Implications in Cardiovascular Health.
    Yajun Wang, Rong Tian.
      Mitochondria are important organelles for metabolic homeostasis, cell fate, and survival. Emerging evidence suggests that mitochondria are not confined to the cells. Intercellular mitochondrial transfer (IMT) is increasingly recognized between a variety of cells, including major cell types in the cardiovascular system. Observations made by coculture systems, genetic lineage-tracing approaches, and animal models indicate that mitochondria can be transferred between cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, cardiac macrophages, and mesenchymal stromal cells. IMT has also been reported between a remote organ, for example, adipose tissue, and the heart, suggesting that mitochondrial trafficking can mediate communications not only between individual cells but also across organs. Two principal modes of IMT are reported. One involves directed, contact-dependent trafficking of mitochondria through membranous contacts or nanotubes. The other relies on the release of mitochondria, either packaged in membrane-bound vesicles or as free mitochondria, into the extracellular space followed by import into the acceptor cells. Consequences of IMT can be beneficial or detrimental depending on the cell type and the conditions under which the IMT occurs. Mechanisms underlying the transfer or its consequences are not fully understood, however. The role of IMT in cardiovascular health is, therefore, interpreted with certain assumptions. In this review, we first summarize the evidence of IMT in the cardiovascular system and the observed functional outcome. We then aim to identify the knowledge gaps and critical questions to be addressed, followed by a discussion of challenges and opportunities to advance the field.
    Keywords:  cardiovascular system; cell communication; extracellular vesicles; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326986
  45. Nat Commun. 2026 Apr 04.
    Mechanisms of human mitochondrial leaderless mRNA translation initiation.
    Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.
      Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNAMet before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNAMet and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.
    DOI:  https://doi.org/10.1038/s41467-026-71535-4
  46. bioRxiv. 2026 Mar 12. pii: 2026.03.11.711168. [Epub ahead of print]
    Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.
    Juyeong Cho, Rebecca Danner, Woo Sung Kim, Jonathan Williams, Anshit Singh, Jiyoung A Han, Jonathan G Van Vranken, Allison S Walker, Timothy Rhoads, Snehal N Chaudhari.
      Methotrexate (MTX) therapy in inflammatory bowel disease (IBD) is often limited by inter-individual variability in clinical response and adverse effects. Gut microbiota contribute to MTX therapeutic response and toxicity by metabolizing MTX and altering its bioavailability. However, how inflammation alters microbial MTX metabolism and how its metabolites influence the host remain poorly understood. Here, we identify Clostridium asparagiforme as a potent and efficient metabolizer of methotrexate, producing deoxyaminopteroic acid (DAMPA) in the distal gastrointestinal tract. We demonstrate that DAMPA preserves mitochondrial integrity by promoting mitophagy in intestinal epithelial cells through mitochondrial STAT3 signaling. DAMPA administration attenuates intestinal inflammation in vivo , and improves metabolic dysfunction associated with IBD. Together, these findings reveal an unappreciated role for a gut microbial MTX metabolite in mediating epithelial homeostasis during intestinal inflammation, thus reframing microbial MTX metabolism from passive drug detoxification to active regulation of host mitochondrial and inflammatory homeostasis.
    DOI:  https://doi.org/10.64898/2026.03.11.711168
  47. bioRxiv. 2026 Mar 30. pii: 2026.03.28.714855. [Epub ahead of print]
    Dissecting Complex Interactions Between Ferroptosis and the Proteasome.
    Magdalena B Murray, Rishi Upadhyay, Krystina Szylo, Aastha Gautam, Judith Goncalves, Giovanni Forcina, Ananya Vinayak, Onn Brandmann, Scott J Dixon.
      The proteasome is an essential multiprotein complex whose inhibition can lead to apoptosis. Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. How proteasome function regulates ferroptosis sensitivity is poorly understood and difficult to study given the essential nature of the proteasome. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining direct cell death imaging, cell death pathway-specific inhibitors, and mathematical modeling. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system x - inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. This work demonstrates a complex role for proteasome function in ferroptosis regulation and establishes new methods to dissect cross-talk between ferroptosis and essential cellular processes.
    DOI:  https://doi.org/10.64898/2026.03.28.714855
  48. Nat Commun. 2026 Apr 04.
    Repulsion from slow-diffusing nutrients improves microbial chemotaxis towards moving sources.
    Blox Bloxham, Hyunseok Lee, Jeff Gore.
      Chemotaxis, or the following of chemical concentration gradients, is essential for microbes to locate nutrients. However, microbes often display paradoxical behaviors, such as Escherichia coli being repelled by several amino acids. Here, we explore chemotaxis towards a moving source and demonstrate that when multiple nutrients are released from the source repulsion from certain nutrients actually improves chemotaxis towards the source. Because a moving source leaves most of the nutrient plume behind it, simply following the concentration gradient results in aiming behind the source and potentially failing to intercept it. However, when attraction to a fast-diffusing nutrient and repulsion from a slow-diffusing nutrient are combined, motion in a new direction emerges and the chance of intercepting the source is increased up to six-fold. We demonstrate that this "differential strategy" is robust against numerous variations, including order-of-magnitude increases in the repellent release rate. Finally, we leverage existing data to show that E. coli is attracted to fast-diffusing amino acids and repelled by slow-diffusing ones, suggesting it may utilize a differential strategy and providing an explanation for its repulsion from these amino acids. Our results thus illuminate new possibilities in how microbes can integrate signals from multiple gradients to accomplish challenging chemotactic tasks.
    DOI:  https://doi.org/10.1038/s41467-026-71148-x
  49. Sci Adv. 2026 Apr 10. 12(15): eaec4368
    SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth.
    Mengyao Qin, Longcheng Shang, Hao Chen, Li Shi, Chan Liu, Ming Ding, Dandan He, Chang Shao, Shengtao Yuan, Hong Yu, Haiping Hao, Yong Ma, Jing Xiong.
      Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.
    DOI:  https://doi.org/10.1126/sciadv.aec4368
  50. JCI Insight. 2026 Apr 09. pii: e195384. [Epub ahead of print]
    Loss of Tumor-Infiltrating Lymphocytes and Poor Response to Immunotherapy in IDH GOF Mutant Melanoma.
    Emma Specht, Lakshmi Pakanati, Meng-Ju Wu, Russell W Jenkins, Derek N Effiom, Nabeel Bardeesy, Bradley E Bernstein, Moshe Sade-Feldman, Christine G Lian, Genevieve M Boland, Elena Torlai Triglia, Sonia Cohen.
      Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients, however over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance, and never respond to therapy, or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data shows that isocitrate dehydrogenase gain of function (IDH GOF) mutant melanoma patients have a worse response to anti-PD1 immunotherapy. IDH mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of IDH GOF melanomas through analyses of clinical response, single-cell RNA sequencing, bulk RNA sequencing, and DNA methylation data. Single-cell data analysis shows decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrates the association between IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented supports previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration of the role of IDH GOF in the human melanoma tumor microenvironment.
    Keywords:  Cancer immunotherapy; Epigenetics; Genetics; Immunology; Melanoma; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.195384
  51. Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217
    Exercise induces sex-specific assembly of mitochondrial supercomplexes.
    Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.
      The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.
    Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117217
  52. Commun Biol. 2026 Apr 10.
    Ferroptosis as a therapeutic vulnerability in ARID1A-deficient bladder cancer.
    Mengxue Zhao, Xuefeng Wang, Xianbin Duan, Chunyue Wu, Rui Guo, Yan Wen, Jiaxin Liang, Jie Zhou, Xuefen Lei, Shi Fu, Haifeng Wang, Cheng Peng, Chunming Guo.
      ARID1A is among the most frequently mutated genes in bladder cancer, yet no targeted therapy exists for this molecular subset. Here, we identify ferroptosis induction as a synthetic lethal strategy in ARID1A-deficient bladder cancer. We found that ARID1A loss impaired the NRF2-SLC7A11-glutathione (GSH) axis, leading to redox imbalance and profound sensitivity to the ferroptosis inducer RSL-3. In vitro, ARID1A knockdown depleted intracellular GSH and enhanced RSL-3-induced lipid peroxidation and cell death. Mechanistically, ARID1A directly regulated NRF2 transcription and its target SLC7A11, and restoring SLC7A11 or NRF2 activity or GSH levels rescued ferroptosis sensitivity. In vivo, RSL-3 treatment delayed tumor progression, reduced muscle invasion, and improved survival in two types of Arid1a -deficient mouse models. Furthermore, patient-derived organoids from ARID1A-low human tumors exhibited heightened RSL-3 sensitivity rather than ARID1A-high tumor. Our findings establish ferroptosis as a targetable vulnerability in ARID1A-deficient bladder cancer and provide a compelling rationale for clinical translation of ferroptosis-based therapies in this molecularly defined population.
    DOI:  https://doi.org/10.1038/s42003-026-09998-w
  53. Cell Commun Signal. 2026 Apr 06.
    Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
    Eve Harding, Veronica Bazzani, Carlo Vascotto.
      
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling
    DOI:  https://doi.org/10.1186/s12964-026-02858-4
  54. Science. 2026 Apr 09. 392(6794): eady3136
    Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration.
    Byron W H Mui, Joseph J Y Wong, Camille E Dumas, Jia Hua Wang, Toni Bray, Kentaro Hirose, Lauren Connolly, Alexander Winkel, Sebastian Timmler, Nicholas A Bright, Evelina Sliauteryte, Ragnhildur Thóra Káradóttir, Pamela G Robey, Kristian Franze, Kevin J Chalut, Mekayla A Storer.
      Tissue regeneration is rare in mammals, but the digit tip can regrow after amputation, whereas injuries beyond the nail do not. How the microenvironment drives divergent outcomes remains unclear. In this study, we found that the extracellular matrix (ECM) and tissue mechanics govern the amputation response in mouse digits. Nonregenerative regions were stiffer and contained dense, organized collagen, whereas regenerative regions were soft and enriched in hyaluronic acid (HA). Depleting HA inhibited regeneration and promoted fibrosis, demonstrating that the HA-collagen balance shaped tissue mechanics and repair signaling. Stabilization of HA with hyaluronan and proteoglycan link protein 1 (HAPLN1) after nonregenerative amputations tuned ECM mechanics, reduced scarring, and enhanced bone repair. Thus, ECM composition and mechanics influence cell behavior and ECM-targeted strategies could help unlock mammalian regeneration.
    DOI:  https://doi.org/10.1126/science.ady3136
  55. bioRxiv. 2026 Mar 15. pii: 2026.03.13.711608. [Epub ahead of print]
    Uncovering cancer dependencies in peptide-interacting protein pockets.
    Mihkel Örd, Liz Kogan, Devin Bradburn, Michelle Leiser, Mardo Kõivomägi, Norman E Davey, Pau Creixell.
      Cancer cells often become dependent on specific molecular functions. As many proteins perform multiple functions mediated by different pockets and interfaces, we hypothesized that we could identify distinct cancer dependencies and therapeutic vulnerabilities by disrupting peptide-binding pockets. To test this hypothesis, we screened a proteome-wide library of 7152 genetically encoded peptides across nine cancer cell lines. We identify common and selective dependencies on peptide-binding pockets and find that gene knockout and peptide-mediated inhibition of pockets often drive divergent phenotypes. For the common-essential gene HCF1, we identify a therapeutic window by using inhibitory peptides with varying affinity. Moreover, peptides targeting TLE1-4 reveal a dependency hidden in genetic screens by homolog redundancy. We also uncover that peptides inhibiting cyclin D drive specific suppression of leukemia cell proliferation and demonstrate that these peptides improve the potency of CDK4/6 inhibitors. Overall, our screening platform facilitates data-driven prioritization of molecular pockets for subsequent therapeutic translation.
    DOI:  https://doi.org/10.64898/2026.03.13.711608
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