bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–08–09
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
  2. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  3. The microenvironment dictates glyco-immune surveillance via HSF1-mediated metabolism.
  4. Mitochondria with (distinct) personality.
  5. Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
  6. Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
  7. Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
  8. NNMT Loss Drives Cancer Progression by enhancing SAM availability for mTORC1 Signaling and Chromatin Methylation.
  9. A tumour-derived organoid biobank maps cancer gene dependencies.
  10. Metabolic exhaustion and immune ageing in rheumatoid arthritis.
  11. Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
  12. Vorasidenib improves response to subsequent chemoradiation in a genetically engineered mouse model of IDH-mutant glioma.
  13. Career pathways, part 20.
  14. Adaptation of White Adipocytes to Cooler Temperatures: Impacts on Energy Metabolism and Protein Acetylation.
  15. A metabolic view of gastrulation: Coordinating signalling, epigenetics and morphogenesis.
  16. A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
  17. Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer.
  18. Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
  19. MCT4-mediated lactate efflux promotes STING-dependent dendritic cell antitumor immunity.
  20. Spatially resolved tissue architecture and computational pathology in pancreatic cancer.
  21. Community metabolism in dynamic redox landscapes.
  22. The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
  23. Charting intratumor heterogeneity from bench to bedside.
  24. Agent-Based Simulations of Lung Tumor Evolution Suggest That Ongoing Cell Competition Drives Realistic Clonal Expansions.
  25. Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent.
  26. The anti-tumour activity of TNF in melanoma is determined by cFLIP.
  27. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
  28. Pharmacological blockade of oncogenic MAPK activators drives resistance to cystine deprivation with lipid redox remodeling.
  29. Examining the role of extrachromosomal DNA in lung cancer.
  30. Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
  31. Chronic interferon signaling at baseline is associated with acquired resistance to immunotherapy in metastatic melanoma.
  32. Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
  33. The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
  34. Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.
  35. Deep visual multi-omics profiling links morphology and molecular programs in clear cell renal cell carcinoma.
  36. Mannose supports lung cancer metabolism during glycolytic limitation.
  37. Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.
  38. Microenvironmental Prostaglandin F2α Antagonizes FSP1 in Cancer Cells to Sensitize Tumors to Ferroptosis and Immunotherapy.
  39. Pho84/GLUT2 are cellular myo-inositol exporters regulated by inositol pyrophosphates.
  40. Somatic mutations and genome mosaicism in aging and disease.
  41. Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes.
  42. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  43. Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.
  44. Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
  45. A compendium of next-generation patient-derived models for diverse cancers.
  46. Social inequalities linked to accelerated biological aging.
  1. Nat Metab. 2026 Aug 05.
    Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
    Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.
      Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.
    DOI:  https://doi.org/10.1038/s42255-026-01582-0
  2. Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.026
  3. Sci Adv. 2026 Aug 07. 12(32): eaeb1136
    The microenvironment dictates glyco-immune surveillance via HSF1-mediated metabolism.
    Kevin M Tharp, Sangwoo Park, Greg A Timblin, Alicia L Richards, Jordan A Berg, Nicholas M Twells, Nicholas M Riley, Kyle Alvarez, Allen Lee, Egan L Peltan, D Judy Shon, Erica Stevenson, Kimberly Tsui, Francesco Palomba, Austin E Y T Lefebvre, Ross W Soens, Jaya L Thangaraj, Nadia M E Ayad, Joseph A Rhodenhiser, Johanna Ten Hoeve, Kevin Healy, Michelle Digman, Andrew Dillin, Nevan J Krogan, Carolyn R Bertozzi, Dan S Kaufman, Sanju Sinha, Danielle L Swaney, Lara K Mahal, Jason R Cantor, Matthew J Paszek, Valerie M Weaver.
      Altered glucose metabolism is an auspicious feature of solid tumors, but is it an intrinsic property of tumor cells or a metabolic adaptation to the tumor microenvironment? Using normal epithelial cells cultured in a physiological culture medium under conditions that mimic the physical properties of healthy or cancerous tissues, we establish multiomics relationships between the biochemical and physical properties of the microenvironment and its impact on biosynthetic outputs of altered glucose metabolism. We find that microenvironmental properties, such as hyperglycemia, can affect the composition and thickness of the epithelial glycocalyx, in part through the activity of mechanosensitive stress responses associated with Heat Shock Factor 1 (HSF1). Because glycocalyx thickness alters immune surveillance of epithelial-origin tumor cells, we examined the relationship between the HSF1-hyperglycemia axis in human breast tumors and validate it as a druggable vulnerability to license natural killer cell lethality against cancer cells.
    DOI:  https://doi.org/10.1126/sciadv.aeb1136
  4. Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923
    Mitochondria with (distinct) personality.
    Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.
      Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.044
  5. Nat Cell Biol. 2026 Aug 06.
    Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
    Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.
      Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02025-4
  6. Genes Dev. 2026 Aug 06.
    Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
    Caleb Cheng, Rüya Pakkan, Arul M Chinnaiyan, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor-host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.
    Keywords:  lysosome metabolism; pancreatic cancer; tumor host metabolism
    DOI:  https://doi.org/10.1101/gad.353702.126
  7. Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14
    Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
    Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.
      Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.
    Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.106492
  8. bioRxiv. 2026 Jul 01. pii: 2026.06.30.734970. [Epub ahead of print]
    NNMT Loss Drives Cancer Progression by enhancing SAM availability for mTORC1 Signaling and Chromatin Methylation.
    Qu Deng, Erick Mitchell-Velásquez, Sharan Venkatesh, Rahul Mannan, Hyein Cho, Mohammed Alhusayan, Aqsa Yashfeen, Ramakrishnan Natesan, Natarajan V Bhanu, Radha Paturu, Javed Siddique, Rohit Mehra, Sooryanarayana Varambally, Benjamin Garcia, David Feldser, Priti Lal, Arul M Chinnaiyan, Irfan A Asangani.
      Aberrant epigenetic reprogramming together with dysregulated mTOR signaling are hallmarks of cancer, where altered chromatin methylation and nutrient-sensing pathways cooperate to drive tumor progression. S-adenosylmethionine (SAM), the universal methyl donor, is essential for these processes, yet how tumors sustain elevated SAM availability to support oncogenic transmethylation reactions remains poorly defined. Here, using prostate cancer (PCa) as a model system, we identify nicotinamide N-methyltransferase (NNMT) as a critical metabolic-epigenetic regulator and tumor suppressor. Using a prostate-specific Nnmt knockout mouse model, we demonstrate that NNMT loss accelerates PCa progression, particularly in the context of Pten deletion, resulting in infiltrating carcinoma and reduced survival. Mechanistically, NNMT functions as a "SAM-sink," and its loss increases intracellular SAM abundance, thereby activating mTORC1 signaling through SAMTOR-dependent sensing and broadly enhancing chromatin methylation. In human PCa, recurrent genomic deletions of NNMT occur in up to 7% of cases, and NNMT protein expression is largely absent in primary tumors and metastases. NNMT-deficient PCa cells exhibit elevated SAM:SAH ratios, increased histone methylation, and heightened mTORC1 activity, enabling sustained tumor growth even under dietary methionine-restriction (MR). Notably, combined MR and pharmacologic mTORC1 inhibition synergistically suppresses the growth of NNMT-deficient tumors, revealing a previously unrecognized therapeutic vulnerability. Collectively, these findings establish NNMT as a key tumor suppressor that constrains SAM-driven epigenetic and signaling programs in PCa and suggest a rational, diet-based therapeutic strategy for advanced cancers with NNMT loss.
    Keywords:  SAM-sink; epigenetics; mTOR signaling; metabolism; prostate cancer; therapeutics; transmethylation
    DOI:  https://doi.org/10.64898/2026.06.30.734970
  9. Nature. 2026 Aug 05.
    A tumour-derived organoid biobank maps cancer gene dependencies.
    OCCAMS Consortium
      Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.
    DOI:  https://doi.org/10.1038/s41586-026-10830-y
  10. Nat Rev Rheumatol. 2026 Aug 03.
    Metabolic exhaustion and immune ageing in rheumatoid arthritis.
    Cornelia M Weyand, Jörg J Goronzy.
      Rheumatoid arthritis (RA) disproportionately affects adults over 50 years of age, highlighting how age-related immune remodelling undermines tolerance and promotes autoreactivity. In later adulthood, immune cells progressively lose metabolic resilience because of impaired nutrient sensing, reduced metabolic flexibility and disrupted anabolic-catabolic balance. In RA, these vulnerabilities are compounded by mitochondrial insufficiency across innate and adaptive immune lineages, creating a state of nutrient deprivation characterized by NAD⁺ and ATP scarcity and diversion of carbon away from oxidative phosphorylation. Mechanistic studies identify this bioenergetic fragility as a core defect that limits cellular longevity and promotes inflammatory, non-apoptotic death pathways, including pyroptosis and PANoptosis. The hypoxic, nutrient-restricted synovial environment adds pressure that exceeds the diminished metabolic adaptability of aged immune cells. In RA T cells, accelerated mitochondrial injury initiates maladaptive stress responses, disrupts mitochondria-lysosome-endoplasmic reticulum communication and induces gasdermin D-dependent pore formation and inflammatory lysis. Synovial MerTK⁺ reparative macrophages undergo a parallel metabolic crisis, whereby autocrine C1q sensing activates mitochondrial SARM1, causing NAD⁺ degradation, ATP depletion and PANoptotic cell death. Together, these findings position ageing-associated metabolic exhaustion and organelle disintegration as unifying mechanisms that convert immune cells into tissue-damaging effectors and explain the heightened susceptibility to RA in older adults.
    DOI:  https://doi.org/10.1038/s41584-026-01402-5
  11. Nat Commun. 2026 Aug 07. pii: 8011. [Epub ahead of print]17(1):
    Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
    Jonathan Kölschbach, Hormos S Dafsari, Emily Baum, Anna Löhrke, Chun Kew, Ivan Dikic, Wenming Huang, Adam Antebi.
      mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.
    DOI:  https://doi.org/10.1038/s41467-026-76295-9
  12. Sci Transl Med. 2026 Aug 05. 18(861): eaee5876
    Vorasidenib improves response to subsequent chemoradiation in a genetically engineered mouse model of IDH-mutant glioma.
    Diana D Shi, Ester Calvo Fernández, Vinesh T Puliyappadamba, Tyler A Lanman, Yi Xiao, Zebin Wen, Maria Minor, Diego Prost, Aleksandra B Lasica, Feng Cai, Ethan Neumann, Sriram Gudipelly, Louise M Clark, Quang-De Nguyen, Salvador Peña, Janaka Wansapura, Pranita Kaphle, Tracey Shipman, Michael M Levitt, Mathew D Lin, Alexander C-Y Tsai, Joyce H Lee, Daniel P Cahill, Rifaquat Rahman, Daphne A Haas-Kogan, Timothy E Richardson, Itay Tirosh, Payal Jain, Adriana E Tron, Vihang Nakhate, Gilbert Youssef, Caroline Dehais, Julian Jacob, David A Reardon, Julie J Miller, Kalil G Abdullah, Patrick Y Wen, Ralph J DeBerardinis, Lin Xu, Mehdi Touat, Katherine B Peters, L Nicolas Gonzalez Castro, William G Kaelin, Mario L Suvà, Samuel K McBrayer.
      The mutant isocitrate dehydrogenase 1/2 inhibitor (mIDHi) vorasidenib was recently incorporated into clinical treatment guidelines for IDH-mutant gliomas, although its impact on chemoradiation is unclear. Specifically, it is unknown whether upfront mIDHi exposure alters subsequent chemoradiation efficacy. Addressing this critical question has been challenging because of limited clinical data and a paucity of mIDHi-responsive preclinical glioma models. We first established that a genetic mouse model of IDH-mutant astrocytoma developed by our group was responsive to vorasidenib monotherapy. We then used this mouse to address whether mIDHi alters the response to chemoradiation after progression on mIDHi. Mice that received upfront vorasidenib followed by chemoradiation at progression had improved survival compared with control mice receiving vehicle followed by chemoradiation. We then compiled real-world data and early outcomes from 29 patients who were among the first to receive mIDHi followed by radiation with or without chemotherapy. Our study directly addresses uncertainty surrounding therapy sequencing that has emerged after introduction of vorasidenib as a first-line treatment for IDH-mutant glioma. Our empirical preclinical data demonstrate that prior mIDHi treatment enhances chemoradiation sensitivity of IDH-mutant glioma.
    DOI:  https://doi.org/10.1126/scitranslmed.aee5876
  13. Nat Metab. 2026 Aug 07.
    Career pathways, part 20.
    Adelheid Lempradl, Lauren V Albrecht.
      
    DOI:  https://doi.org/10.1038/s42255-026-01596-8
  14. FASEB J. 2026 Aug 15. 40(15): e72164
    Adaptation of White Adipocytes to Cooler Temperatures: Impacts on Energy Metabolism and Protein Acetylation.
    Hiroyuki Mori, Hadla Hariri, William Moe, Sophia Durham, Yuridia Guzman, Emma Paulsson, Rachel C Simmermon, Parth B Bhanderi, Sydney K Peterson, Mia J Dickson, Charles R Evans, Ormond A MacDougald.
      Adipocytes throughout the body reside in distinct thermal environments. Visceral adipocytes within the body core are maintained near 37°C, whereas those in bone marrow, subcutaneous, and dermal depots occupy cooler regions within the peripheral shell. Although brown and beige adipocyte responses to cold stress are well characterized, much less is known about how white adipocytes adapt to moderately reduced temperatures below 37°C. Our recent work revealed that cultured adipocytes exposed to 31°C, a temperature representative of distal adipose regions, exhibit enhanced mitochondrial function, including increased substrate oxidation and ATP turnover, yet the mechanisms underlying this upregulation remain unclear. Here we show that adaptation to cool temperatures leads to a widespread decrease in protein acetylation in both undifferentiated and differentiated adipocytes, independent of nutrient status, and that this change is readily reversible upon rewarming. Subcellular fractionation and immunoblotting demonstrate that the hypoacetylation coincides with a compartment-specific enrichment of acetylated proteins within mitochondria, indicating selective remodeling of the mitochondrial acetylome. Transcriptomic and biochemical analyses reveal that these temperature-dependent changes occur without alterations in acetyltransferase or deacetylase expression, NAD+ concentration, or acetyl-CoA availability, suggesting regulation through alternative mechanisms affecting acetyl-CoA flux or enzyme activity. Integrative acetyl-proteomic and metabolomic profiling identifies mitochondrial enzymes, including serine hydroxymethyltransferase 2 (SHMT2) and propionyl-CoA carboxylase α (PCCA), whose acetylation correlates closely with changes in associated metabolite pools. Together, these findings establish physiologically relevant cooling as a cell-autonomous regulator of mitochondrial protein acetylation and metabolic adaptation in adipocytes.
    Keywords:  PCCA; SHMT2; adipocytes; cool‐temperature adaptation; metabolic remodeling; mitochondrial function; protein acetylation
    DOI:  https://doi.org/10.1096/fj.202601941R
  15. Semin Cell Dev Biol. 2026 Aug 05. pii: S1084-9521(26)00022-4. [Epub ahead of print]184 103688
    A metabolic view of gastrulation: Coordinating signalling, epigenetics and morphogenesis.
    Tatiana Firfa, Tamara Civetta, Eunice HoYee Chan, Kristina S Stapornwongkul.
      Gastrulation is the morphogenetic process by which the single-layered pluripotent epiblast is reorganised into the three germ layers and the basic body plan is established. While the metabolic state of pluripotent stem cells is well characterised, the metabolic remodelling that coincides with germ layer specification is less well understood. Emerging evidence suggests that metabolism functions as more than a passive housekeeping process and instead acts as a dynamic regulator of cell state during these developmental transitions. Here, we review recent work that implicates a role for metabolic pathways in regulating cell fate and morphogenesis during gastrulation. In particular, glucose metabolism appears to serve as a critical regulatory layer, modulating morphogen signalling to promote the emergence and function of mesodermal and endodermal populations. We also discuss the role of the tricarboxylic acid cycle and one-carbon metabolism in epigenetic remodelling and highlight the role of lipid metabolism in coupling the biophysical properties of membranes to cellular identity and morphogenetic movements. A current challenge is to distinguish in which situations metabolic shifts act as instructive drivers or permissive gatekeepers of development. Technological advances in spatial metabolomics, biosensors, and optogenetics are now facilitating the visualisation and manipulation of metabolic activity, paving the way for a mechanistic understanding of how metabolism shapes cell fate and behaviour during gastrulation.
    Keywords:  EMT; Energetics; Epimetabolites; Gastrulation; Germ layer specification; Metabolic signalling; Metabolism
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103688
  16. Cancer Cell. 2026 Aug 03. pii: S1535-6108(26)00312-0. [Epub ahead of print]
    A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
    Yang Zheng, Caleb Cheng, Yizhi Cao, Gabriel Cruz, Yuping Zhang, Radha Paturu, Somnath Mahapatra, Jing Hu, Rahul Mannan, Hüseyin Karabürk, Rupam Bhattacharyya, Yitong Yin, Yi Zhao, Wenyan Liu, Xuhong Cao, Hui Xue, Chungen Li, Zhen Wang, Stephanie J Miner, Zachery R Reichert, Rohit Mehra, Ulka Vaishampayan, Vaibhav Sahai, Lois S Weisman, Ke Ding, Costas A Lyssiotis, Yuzhuo Wang, Arul M Chinnaiyan, Yuanyuan Qiao.
      Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-adaptive lipid kinase axis that supports adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, exacerbates ER stress, and activates a compensatory sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
    Keywords:  PI(3,5)P(2); PIKfyve; SREBP; autophagy; endoplasmic reticulum stress; fatty acid synthase; lipid metabolism; lysosome; neuroendocrine prostate cancer; unfolded protein response
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.003
  17. Cell. 2026 Aug 05. pii: S0092-8674(26)00863-9. [Epub ahead of print]
    Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer.
    Shorook Naara, Veena Kochat, Xiayu Rao, Emre Arslan, Robert Saddawi-Konefka, Suresh Satpati, Jennifer Garbarino, Jennifer L Anderson, Frederico O Gleber-Netto, Priyadharsini Nagarajan, Travis D Kerr, Shamima Akhter, Sophie Li, R'ay Fodor, Shlomo A Koyfman, Dan Yaniv, Tongxin Xie, Mica Glaun, Michael Bobian, William Israel Padron, Colin Ng, Preethi H Gunaratne, Shiyanth Thevasagayampillai, Michael R Migden, Hussein A Abbas, Patrick K Reville, Kenneth Y Tsai, Daniel J McGrail, Jing Wang, Jeffrey N Myers, Neil D Gross, Kunal Rai, Moran Amit.
      Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.
    Keywords:  BCC; NMSC; cSCC; immunosuppression; immunotherapy; macrophage; skin cancer; spatial epigenomics; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2026.07.031
  18. Crit Rev Oncol Hematol. 2026 Aug 06. pii: S1040-8428(26)00417-8. [Epub ahead of print] 105530
    Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
    Sijia Feng, Yanan Hu, Shuqing Li, Yuqiao Chang, Zhenwei Li, Yanting Liu, Kai Xu.
      Mitochondrial transfer has emerged as a previously underappreciated layer of intercellular communication within the tumor microenvironment. Accumulating evidence demonstrates its contribution to the metabolic and functional plasticity of both tumor and immune cells. Rather than representing a rare stochastic event, mitochondrial exchange occurs across multiple cell types-including cancer cells, stromal cells, and infiltrating immune cells-via distinct structures such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and transient cell fusion events. In tumor cells, acquisition of exogenous mitochondria is commonly associated with enhanced oxidative phosphorylation (OXPHOS), improved metabolic adaptation, and increased tolerance to therapeutic stress. Conversely, immune cells that undergo mitochondrial depletion or receive dysfunctional mitochondria frequently display impaired bioenergetic capacity and diminished effector function, thereby contributing to immune dysfunction in the TME. Recent advances in intravital imaging, single-cell technologies, and lineage tracing have provided compelling evidence that mitochondrial transfer is a dynamic, context-dependent and often directional process. Beyond metabolic effects, mitochondrial components, particularly mitochondrial DNA (mtDNA), can engage innate immune pathways including TLR9, NLRP3, and cGAS-STING, thus modulating inflammatory signaling and antitumor immunity. Overall, mitochondrial transfer functions as a bidirectional regulator of immunometabolic states in cancer, with potential either to support tumor progression or to modulate immune responses, depending on cellular context. Understanding the molecular determinants governing this process may offer opportunities to selectively target pathological mitochondrial exchange or to exploit it for therapeutic benefit in cancer immunotherapy. This comprehensive review examines the molecular mechanisms, immunological consequences, and therapeutic implications of mitochondrial transfer in cancer.
    Keywords:  extracellular vesicles; metabolism; mitochondrial transfer; tumor immune microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105530
  19. Cell Rep. 2026 Aug 01. pii: S2211-1247(26)00856-9. [Epub ahead of print]45(8): 117778
    MCT4-mediated lactate efflux promotes STING-dependent dendritic cell antitumor immunity.
    Rui Ding, Yaqing Yuan, Tongchang Xu, Jingwen Zhang, Yi Zhu, Bing Yao, Shuang Qu, Zhilin Hu.
      The mechanisms by which DCs evolutionarily adapt to lactate accumulation to maintain their functions remain largely elusive. Here, our study highlights the MCT4-lactate axis as an intrinsic metabolic checkpoint governing intratumoral DC activity. Intratumoral lactate supplementation impedes DC-dependent antitumor activity. Additionally, we observe that MCT4 is highly expressed in intratumoral DCs and mediates lactate efflux to boost DC function. Pharmacological or genetic inhibition of MCT4 suppresses DC antitumor responses. Mechanistically, MCT4-controlled lactate efflux sustains STING signaling and STING-dependent antitumor immunity. Loss of MCT4 in DCs augments lactate accumulation, subsequently reducing intracellular pH and disrupting the interaction between G3BP1 and cGAS, ultimately leading to impaired dsDNA sensing by cGAS. Importantly, the MCT4-lactate axis supports STING-dependent DC activity in ccRCC patient samples. Our findings uncover how intratumoral DCs adapt to lactate and suggest that targeting the MCT4-lactate axis represents a promising cancer immunotherapy strategy.
    Keywords:  CP: cancer; CP: immunology; MCT4; antitumor immunity; cGAS-STING; dendritic cells; lactate
    DOI:  https://doi.org/10.1016/j.celrep.2026.117778
  20. Exp Mol Med. 2026 Aug 04.
    Spatially resolved tissue architecture and computational pathology in pancreatic cancer.
    Seong-Woo Bae, Aristotelis Tsirigos, Jimin Min, Anirban Maitra.
      Pancreatic ductal adenocarcinoma (PDAC) is a complex disease characterized by high levels of cellular heterogeneity and pronounced microenvironmental remodelling. Dynamic changes during its initiation and progression contribute to resistance to conventional therapies. Building upon key molecular catalogues established by bulk and single-cell profiling studies that have advanced our understanding of PDAC biology, recent advances in spatial biology have provided much-needed insights by elucidating regionally compartmentalized transcriptomic and proteomic programmes within the PDAC microenvironment. In parallel, emerging computational frameworks in digital pathology and artificial intelligence have advanced the field into a high-dimensional, quantitative discipline, particularly for classifying molecular and clinical features from histopathology images. Despite these advancements, integration of these two modalities remains a major challenge. Here, we summarize the convergence of molecular features identified through spatially resolved profiling in PDAC and its precursor lesions, as well as current developments in AI-powered pathology in cancer research. We further propose a multi-modal integration framework that maps molecular states onto morphological and architectural phenotypes, offering a roadmap for spatially informed patient stratification beyond descriptive tissue characterization. We posit that the path forward relies on disciplined cross-scale integration of spatial, histological, and clinical data to ensure meaningful translation into clinical practice.
    DOI:  https://doi.org/10.1038/s12276-026-01782-4
  21. Curr Opin Microbiol. 2026 Aug 07. pii: S1369-5274(26)00098-6. [Epub ahead of print]93 102804
    Community metabolism in dynamic redox landscapes.
    Alberto Scarampi, Jonas Cremer, Orkun S Soyer.
      Microbial communities are fundamentally shaped by the diverse metabolic processes through which microbes extract energy from the chemical and light-driven potential gradients in their environment. Thus, predicting microbial community dynamics requires a quantitative framework grounded in bioenergetics and accounting for the key factors influencing metabolite concentrations in microbes' local environment. Here, we present a perspective based on three tightly coupled factors governing microbial community metabolism: (i) the thermodynamics of redox reactions, that is, the redox tower, as a universal constraint on energy yield and reaction feasibility; (ii) external environmental and host-driven factors that set the availability of key metabolites that can act as electron donors and acceptors; and (iii) intracommunity cellular responses that alter metabolic outputs and feedback with local conditions. We emphasise that all three factors have to be integrated and considering any one without the others will only provide limited insights into community metabolisms. This integrative view needs to be incorporated into tightly coupled experiments and modelling to enable a mechanistic understanding of microbial community metabolism across environments.
    DOI:  https://doi.org/10.1016/j.mib.2026.102804
  22. Cell Rep. 2026 Aug 05. pii: S2211-1247(26)00869-7. [Epub ahead of print]45(8): 117791
    The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
    Ling He, Hongying An, Karina Ramirez, Sally Radovick, Fredric E Wondisford.
      Metformin is the first-line oral anti-diabetic agent. Metformin concentrations in the intestine can reach up to 1.3 mM, while those in the portal vein are approximately 0.075 mM. It is unclear whether this metformin concentration difference contributes to metformin's antidiabetic effects. Here, we showed that high metformin concentrations upregulate G6PC expression through AMP-activated protein kinase (AMPK) activation to prevent glucose release in intestinal epithelial cells (IECs). The inhibition of mitochondrial activity by high metformin concentrations leads to drastically increased glucose utilization through glycolysis, along with lactate overproduction in the IECs. Subsequently, glycolytic metabolite lactate is released from IECs into portal vein and delivered to the liver. In the liver, low concentrations of metformin activate AMPK to promote mitochondrial fission and mitophagy to maintain a healthy mitochondrial population, resulting in increased lactate utilization in the mitochondria. These coordinated actions of metformin in the intestine and liver improve hyperglycemia in diabetes and obesity.
    Keywords:  CP: metabolism; insulin sensitivity; intestine epithelial cells; lactate overproduction; metformin action; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117791
  23. Nat Cancer. 2026 Aug 07.
    Charting intratumor heterogeneity from bench to bedside.
    Jonathan C M Wan, Nicholas McGranahan, Charles Swanton.
      Intratumor heterogeneity poses a fundamental challenge across the cancer care continuum, from diagnosis to treatment resistance and metastasis. Over recent decades, multiregion and multiomic profiling of tissue, together with functional studies and longitudinal plasma sampling, have revealed the dynamic and multidimensional evolution of tumor ecosystems. This complexity spans genetic and non-genetic mechanisms within cancer cells and their microenvironment. In this Review, we synthesize the current understanding of heterogeneity and evolution and discuss how these insights can inform the development of evolution-aware diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43018-026-01198-z
  24. Adv Sci (Weinh). 2026 Aug 06. e76764
    Agent-Based Simulations of Lung Tumor Evolution Suggest That Ongoing Cell Competition Drives Realistic Clonal Expansions.
    Helena Coggan, James R M Black, Carlos Martínez-Ruiz, Kristiana Grigoriadis, Jasmin Fisher, Nicholas McGranahan.
      Computational simulations of tumor evolution are increasingly used to infer the rules underlying cancer growth. To make reliable inferences, such models must be able to reflect the properties of real tumors. Recent work has shown that lung tumors undergo frequent and late subclonal expansions, which are associated with poor prognosis. This paper tests three candidate simulations of three-dimensional tumor growth, which make different assumptions about the nature of competition between cells, for their ability to replicate these late expansions. The study identifies a computationally-efficient model which can produce multi-region sequencing data realistic to lung tumors. This model assumes two distinct stages of growth, with the second stage involving local competition for space and resources within and between small tissue areas in a fixed-size tumor. When inferring the model-specific fitness effect of driver mutations in a large cohort of lung cancers, the study finds that inference pipelines based on a two-stage model imply much larger selection effects than those based on single-stage models, driven by model-specific assumptions about the practical consequences of selection strength. This work emphasizes the importance of model assumptions to the results of tumor-specific, simulation-based inferences.
    Keywords:  agent‐based models; lung cancer; tumor evolution
    DOI:  https://doi.org/10.1002/advs.76764
  25. Sci Adv. 2026 Aug 07. 12(32): eaef3128
    Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent.
    Natalia Mrnjavac, Nadja K Hoffmann, Manon L Schlikker, Maximilian Burmeister, Loraine Schwander, Carolina García García, Max Brabender, Mike Steel, Daniel H Huson, Sabine Metzger, Quentin Dherbassy, Bernhard Schink, Mirko Basen, Joseph Moran, Harun Tüysüz, Martina Preiner, William F Martin.
      The origin of life required the emergence of metabolism, an autocatalytic network of enzymatic reactions that synthesize amino acids, nucleotides, and cofactors. At the origin of metabolism, there were no enzymes-how did it start? Empirical studies addressing early metabolic evolution are lacking. Harnessing protein structures for metabolic enzymes, we identify intermediate states in primordial metabolic assembly. We show that enzymatic metabolism in the universal common ancestor was incomplete, undergoing final assembly independently in the lineages leading to bacteria and archaea. Native transition metals-iron, cobalt, nickel, and palladium-served as the catalytic forerunners of both enzymes and cofactors at metabolic origin, while phosphite supplied energy, as it phosphorylates adenosine 5'-monophosphate to adenosine 5'-diphosphate and serine to phosphoserine using native metal catalysts in water. Phosphite and native metals occur in serpentinizing hydrothermal systems, identifying an energy-supplying, catalytic site of metabolic origin. Cofactors liberated nascent metabolism from native metal catalysts, engendering its autocatalytic state.
    DOI:  https://doi.org/10.1126/sciadv.aef3128
  26. Cell Death Dis. 2026 Aug 01. pii: 671. [Epub ahead of print]17(1):
    The anti-tumour activity of TNF in melanoma is determined by cFLIP.
    Johanna Stachelscheid, Cäcilia Kaul, Katrin Gerstenberg, J Paul Werthenbach, Fabian Schorn, Joy Steinkamp, Paola Zigrino, Manolis Pasparakis, Lars M Schiffmann, Hamid Kashkar.
      Tumour necrosis factor (TNF) is a pleiotropic cytokine originally identified for its ability to kill cancer cells. However, a paradoxical tumour-promoting role for TNF emerged when early attempts to exploit its anti-tumour activity in cancer therapy produced conflicting outcomes, raising the question of whether TNF should be viewed as a therapeutic agent or a treatment target in cancer. Here, we demonstrate that expression of cFLIP, a catalytically inactive paralogue of caspase-8 (CASP8), determines the susceptibility of melanoma cells to TNF and thereby controls melanoma growth in a syngeneic, immune-competent mouse model of B16F10 cutaneous melanoma. B16F10 melanoma cells lacking cFLIP (cFlipKO/KO cells) failed to grow in wild-type mice, whereas in TNF-deficient mice, cFlipKO/KO melanoma cells formed palpable tumours and exhibited robust subcutaneous growth. These findings indicate that TNF alone is sufficient to control melanoma growth in the absence of cFLIP. Importantly, the anti-tumour activity of TNF has predominantly been investigated through targeting cellular inhibitors of apoptosis proteins (cIAPs), which promotes RIPK1 activation and TNF-induced cytotoxicity. We show that genomic ablation of cIAPs or RIPK1, in contrast to cFLIP, neither triggered TNF-induced toxicity nor affected melanoma growth in vivo. Collectively, our data underscore the central role of cFLIP in regulating melanoma responses to TNF and suggest that endogenous immune surveillance as well as immunotherapies involving TNF could strongly benefit from cFLIP targeting strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09154-6
  27. Nature. 2026 Aug 05.
    ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
    Qingwen Jiang, Manisha S Raghavan, Aileen M Rodriguez, Morgan Lallo, Cyrus L Tam, Saskia Hartner, Britney Forsyth, Ahmed Mahmoud, Fabian Zincke, Huiyong Zhao, Andrew Moorman, Sasha Balkaran, Kathleen Luckett, Jura Pintar, Yevgeniy Romin, Eric Chan, Anthony Santella, Bernadette Mödl, Farheen Shah, Ilyes Baali, Michael G Kharas, Elisa de Stanchina, Nil Urganci, Jinru Shia, Dana Pe'er, Francisco Sanchez-Vega, Richard Koche, Quaid Morris, Joseph M Chan, Karuna Ganesh.
      Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.
    DOI:  https://doi.org/10.1038/s41586-026-10890-0
  28. Biochem Biophys Res Commun. 2026 Jul 31. pii: S0006-291X(26)01140-X. [Epub ahead of print]832 154376
    Pharmacological blockade of oncogenic MAPK activators drives resistance to cystine deprivation with lipid redox remodeling.
    Tomomiki Noda, Hitomi Shirahama, Yuri Tani, Akihiro Tomida.
      Targeted therapies disrupt oncogenic signaling while inducing adaptive metabolic rewiring for cancer cell survival. However, the roles of acute metabolic shifts remain poorly understood. Here, we showed that inhibiting EGFR, KRAS, or BRAF drove resistance to cystine deprivation-induced ferroptosis in cancer cells harboring each driver mutation. Resistance to cystine deprivation emerged within 24 h of drug treatment and persisted during prolonged 9-day exposure. However, acquiring drug resistance during the 2-month drug exposure abolished the resistance to cystine deprivation, coupled with reactivation of MAPK signaling. Mechanistically, GPX4, which was induced by drug treatment, was crucial to prevent ferroptosis despite a reduction in intracellular cysteine and glutathione levels during cystine deprivation. Additionally, the oncogenic inhibitors altered ALDH isozyme expression profiles, potentially inducing resistance to 4-hydroxynonenal, which is a lipid aldehyde associated with ferroptosis. Our findings identify a novel cellular adaptation mechanism to oncogenic signaling inhibition, providing mechanistic insights into how cancer cells adjust their lipid redox balance during therapy.
    Keywords:  4-HNE; ALDH3B1; Cystine deprivation; Ferroptosis; GPX4; Oncogenic signaling inhibition
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154376
  29. J Natl Cancer Inst. 2026 Aug 05. pii: djag273. [Epub ahead of print]
    Examining the role of extrachromosomal DNA in lung cancer.
    Azhar Khandekar, Phuc H Hoang, Jens Luebeck, Marcos Díaz-Gay, Wei Zhao, John P McElderry, Caleb Hartman, Mona Miraftab, Olivia W Lee, Kara M Barnao, Kristine Jones, Amy Hutchinson, Belynda Hicks, Erik N Bergstrom, Yang Yang, Martin A Nowak, Nathaniel Rothman, Angela C Pesatori, Dario Consonni, Robert Homer, Marina K Baine, Lynette M Sholl, Philippe Joubert, Charles Leduc, William D Travis, Soo-Ryum Yang, Qing Lan, David C Wedge, Lixing Yang, Stephen J Chanock, Tongwu Zhang, Ludmil B Alexandrov, Maria Teresa Landi.
      The role of extrachromosomal DNA (ecDNA) in lung cancer, particularly in subjects who never smoked (LCINS), remains unclear. Examination of over 1200 whole-genome-sequenced lung cancers identified ecDNA in 18.9% of patients. Recurrent amplification of MDM2 and other oncogenes via ecDNA possibly drives a LCINS subset. Tumors harboring ecDNA showed worse overall survival than tumors harboring other focal amplifications. A strong association with whole-genome doubling suggests most ecDNA reflects genomic instability in treatment-naïve lung cancer.
    DOI:  https://doi.org/10.1093/jnci/djag273
  30. J Mol Neurosci. 2026 Aug 05. pii: 124. [Epub ahead of print]76(3):
    Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
    Lishu Guo.
      Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.
    Keywords:  Aging; Mitochondria; Mitochondrial permeability transition; Neurodegeneration; The permeability transition pore
    DOI:  https://doi.org/10.1007/s12031-026-02583-0
  31. Cell Rep Med. 2026 Aug 07. pii: S2666-3791(26)00398-8. [Epub ahead of print] 102981
    Chronic interferon signaling at baseline is associated with acquired resistance to immunotherapy in metastatic melanoma.
    Donagh Egan, Ben Shum, Rabia Fidan, Walter Kolch, Donal Brennan, Irene Lobon, Samra Turajlic.
      Interferons can trigger robust anti-tumor responses following immune checkpoint blockade (ICB). However, chronic interferon signaling can also reshape tumor cell phenotypes, selecting for immune evasion mechanisms that drive resistance. In a cohort of 108 metastatic melanoma samples collected prior to first-line ICB, immune infiltration and bulk interferon gamma (IFNG) expression correlate with initial but not durable responses. Using a regression-based approach to deconvolve cancer cell signals from bulk tumors, we find that tumors from patients who initially respond but later acquire resistance exhibit heightened cancer cell-dependent IFN signaling at baseline, accompanied by MYC downregulation, dedifferentiation, and impaired major histocompatibility complex (MHC) class II induction. Genetically, acquired resistance also associates with reduced T cell interferon signaling, lower memory T cell activity, high tumor mutational burden, clonal diversification, and elevated subclonal neoantigen burden. These findings reveal baseline transcriptomic and genetic features distinguishing acquired resistance from durable ICB response, identifying candidate targets to prevent relapse and refine stratification.
    Keywords:  acquired resistance; durable response; immunotherapy; interferon signaling; intratumor heterogeneity; melanoma; relapse
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102981
  32. RSC Chem Biol. 2026 Jul 13.
    Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
    Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.
      Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed a green fluorescent protein-based intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals the temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.
    DOI:  https://doi.org/10.1039/d6cb00164e
  33. Nat Commun. 2026 Aug 07. pii: 8002. [Epub ahead of print]17(1):
    The Plasmodium heme detoxification protein functions in mitochondrial protein synthesis.
    Louis Sarrazin, Melissa R Rosenthal, Joachim Kloehn, Tanja Ziesmann, Yasmin Schmitz, Anna-Lena Sandtmann, Robert Domènech-Eres, Katharina Scholz-Höhn, Coralie Boulet, Ute Distler, Daniel E Goldberg, Joachim M Matz.
      Malaria blood-stage parasites digest ~80% of host cell hemoglobin within a degradative vacuole, releasing heme that is detoxified by sequestration into hemozoin crystals. Although essential for survival and a validated drug target, the mechanisms of heme biomineralization remain unclear. Here, we study the parasite's Heme Detoxification Protein (HDP), previously proposed to mediate hemozoin formation, using genetic, microscopic, bioenergetic, and proteomic approaches. Endogenous tagging reveals that HDP localizes to the mitochondrion, not the digestive vacuole. HDP inactivation has no effect on heme biomineralization, but causes mitochondrial depolarization, proguanil hypersensitivity, and developmental arrest, which is rescued by bypassing respiratory-chain-dependent pyrimidine biosynthesis. HDP knockout abolishes mitochondrial electron flow due to loss of complexes III and IV, consistent with impaired mitochondrial protein synthesis. Integration of structural modelling with quantitative proteomics places HDP within the mitoribosomal large subunit. Here, we show that HDP is essential for mitochondrial function and does not contribute to hemozoin formation.
    DOI:  https://doi.org/10.1038/s41467-026-76511-6
  34. Immunity. 2026 Aug 03. pii: S1074-7613(26)00307-9. [Epub ahead of print]
    Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.
    Christopher D Balak, Johannes C M Schlachetzki, Addison J Lana, Elizabeth West, Christine Hong, Jordan DuGal, Yi Zhou, Benjamin Li, Nathanael J Spann, Payam Saisan, Vishal Sarsani, Kilian L Kleemann, Xiaoming Zhang, Martina P Pasillas, Sydney O'Brien, Juliette A Bokor, Philip L S M Gordts, Oleg Butovsky, Beth Stevens, Fredrik Kamme, Christopher K Glass.
      Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.
    Keywords:  ChIP-seq; MITF; MPS-IIIA; TFE3; disease-associated microglia; epigenetics; lysosomal storage disorder; lysosome; microglia; neurodegeneration
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.008
  35. EMBO Mol Med. 2026 Aug 06.
    Deep visual multi-omics profiling links morphology and molecular programs in clear cell renal cell carcinoma.
    Hella A Bolck, Ede Migh, Andras Kriston, Natalia Zajac, Susanne Kreutzer, Tiberiu Totu, Peter Leary, Ferenc Kovacs, Dorothea Rutishauser, Sibylle Pfammatter, Jonas Grossmann, Harini Lakshminarayanan, Debleena Basu, Cassandra Litchfield, Marija Buljan, Niels J Rupp, Peter Horvath, Holger Moch.
      Clear cell renal cell carcinoma exhibits striking intra-tumoral heterogeneity at morphological and genetic levels, complicating treatment and contributing to disease progression. CcRCCs with rhabdoid differentiation are highly aggressive tumors characterized by distinct histopathologies. However, the relationship between morphology, underlying molecular alterations, and tumor behavior remains largely unclear. Here, we present Deep Visual Multi-Omics, an approach integrating digital pathology, morphology-guided single-cell isolation, and ultra-sensitive multi-omics profiling to link cell morphologies to their molecular underpinnings. Across five tumors, we profiled ~40,000 AI-classified and expert-curated cells. We identified progressive molecular dysregulation across cells with increasing histopathological grade coexisting within heterogeneous tumors as well as distinct molecular alterations associated with aggressive rhabdoid ccRCC cells, including signatures consistent with enhanced FOXM1-driven proliferation, altered cell-matrix interactions, and a putative immunomodulatory phenotype. Notably, rhabdoid cells exhibited elevated expression of IFN-beta, PD-L1, CD38, ITGB2, and integrin signaling, suggesting that they themselves may act as a source of signals influencing the local immune microenvironment. Besides providing new insights into the biology of ccRCC and highlighting avenues for future translational studies, this illustrates the potential of Deep Visual Multi-omics to dissect cancer heterogeneity and characterize high-risk cell populations.
    DOI:  https://doi.org/10.1038/s44321-026-00484-8
  36. EMBO Rep. 2026 Aug 07.
    Mannose supports lung cancer metabolism during glycolytic limitation.
    Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.
      Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.
    DOI:  https://doi.org/10.1038/s44319-026-00874-6
  37. Drug Resist Updat. 2026 Aug 02. pii: S1368-7646(26)00113-5. [Epub ahead of print]89 101462
    Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.
    Simona Fontana, Dimas Carolina Belisario, Claudia Giannotta, Luca Alessandri, Sabrina Digiovanni, Angelo Meoli, Francesco Passiglia, Alessandra Merlini, Giulianmichela Di Palma, Martina Perin, Francesca Napoli, Maddalena Arigoni, Muhlis Akman, Elisa Balmas, Costanzo Costamagna, Iris Chiara Salaroglio, Joanna Kopecka, Alessandro Bertero, Luisella Righi, Massimo Massaia, Raffaele Calogero, Silvia Novello, Giorgio Vittorio Scagliotti, Yehuda G Assaraf, Chiara Riganti.
       AIMS: Non-small cell lung cancer (NSCLC) patients treated with platinum drugs develop chemoresistance. C/EBPβ has alternative translational LAP and LIP isoforms which impact cancer chemoresistance by modulating ABC efflux transporter expression and activity. Differential alternative translation of LAP:LIP reprograms metabolism in murine embryonic fibroblasts; however, little is known in cancer. To target possible metabolic vulnerabilities, we herein investigated whether LAP/LIP rewires NSCLC cell metabolism towards a chemoresistant phenotype.
    METHODS: LAP- or LIP-overexpressing NSCLC cells were screened for anticancer drug sensitivity, DNA damage and ABC exporter expression and function. Metabolome/lipidome analyses and functional metabolic assays were performed to identify possible chemosensitizing agents. Tumor growth, mass spectrometry imaging and single-cell RNA-sequencing were determined in Hu-CD34+NSG xenografts.
    RESULTS: LAP induced chemoresistance by increasing ABCB1/ABCC1/ABCC2 levels, activity and oxidative DNA damage. Furthermore, LAP altered metabolome and lipidome composition of plasma membrane and mitochondria, and upregulated HADHA and CPT1A, key enzymes in fatty acid oxidation (FAO). The high metabolic flux through FAO and oxidative phosphorylation increased mitochondrial ATP levels, thereby fueling these ATP-driven multidrug efflux pumps. Conversely, LIP displayed the opposite effect. CPT1A knock-out or catalytically-inactive mutant, FAO inhibition with etomoxir or trimetazidine, surmounted chemoresistance. In LAPhigh chemoresistant immune-xenografts, etomoxir redistributed fatty acids within tumor immune-microenvironment (TIME), metabolically reprogrammed NK cells and enhanced their anti-tumor activity.
    CONCLUSION: Increased LAP:LIP ratio induced chemoresistance in NSCLC tumors by instigating a FAO-dependence, unveiling a metabolic vulnerability. FAO inhibition emerges as a novel chemosensitization strategy operating via rewiring tumor and TIME metabolism.
    Keywords:  C/EBP-β; Cisplatin resistance; Fatty acid oxidation; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.drup.2026.101462
  38. Cancer Res. 2026 Aug 06.
    Microenvironmental Prostaglandin F2α Antagonizes FSP1 in Cancer Cells to Sensitize Tumors to Ferroptosis and Immunotherapy.
    Yu Meng, Qian Zhou, Deze Zhao, Hui Su, Jiayuan Le, Daishi Li, Lei Yao, Ziyu Guo, Yixiao Xiong, Yuming Sun, Xiaowei Liang, Furong Zeng, Guangtong Deng, Xiang Chen.
      Induction of ferroptosis is a potential strategy for treating cancer and improving the efficacy of immunotherapy. Ferroptosis is driven by excessive peroxidation of polyunsaturated fatty acid-containing phospholipids, suggesting that microenvironmental lipid metabolites may regulate ferroptotic sensitivity. By integrating single-cell and bulk transcriptomics from immunotherapy cohorts, we identified the prostaglandin (PG) pathway as closely associated with tumor ferroptosis and therapeutic efficacy. Further screening revealed PGF2α as a potent endogenous ferroptosis sensitizer. Mechanistically, microenvironmental PGF2α bound to ferroptosis suppressor protein 1 (FSP1) at alanine 295 (A295) and inhibited its enzymatic activity, leading to lipid peroxidation accumulation upon ferroptotic stimuli. Preclinically, PGF2α supplementation or FSP1 ablation enhanced tumoral ferroptosis, potentiated CD8+ T cell-mediated immunity, and suppressed tumor progression in immunocompetent mice. Moreover, PGF2α improved immunotherapy efficacy across multiple mouse models, including subcutaneous allografts, Braf/Pten-driven spontaneous melanoma, and humanized mice. Clinically, a high PGF2α activity-related transcriptomic signature correlated with elevated ferroptosis and improved patient survival. Collectively, these findings establish PGF2α as a pro-ferroptotic metabolite and propose that targeting the PGF2α/FSP1 axis may offer an effective cancer immunotherapeutic strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5697
  39. EMBO J. 2026 Aug 07.
    Pho84/GLUT2 are cellular myo-inositol exporters regulated by inositol pyrophosphates.
    Xue Bessie Su, Xinjie Zhang, Valeria Fedeli, An-Li Andrea Ko, Jiarui Nicole Fu, Dorothea Fiedler, Adolfo Saiardi.
      Inositol is an essential nutrient for most living organisms, as combinatorial phosphorylation on this cyclic sugar generates key cellular messengers, such as lipid-bound phosphoinositides (PtdInsPs), water-soluble inositol phosphates (InsPs), and high-energy inositol pyrophosphates (PP-InsPs). Although the kinases and phosphatases modifying inositol-derived molecules are well-characterised, the molecular pathways controlling the cellular homeostasis of the inositol backbone and transport carriers remain unclear. Using a combination of LC-MS analysis and a screen based on the inositol-exporting opi1Δ mutant yeast, we here discovered that inositol export is tightly regulated by PP-InsPs and that the high-affinity phosphate transporter Pho84 also acts as an inositol exporter. We further expanded these observations to the mammalian system and revealed that inositol export in human cells is similarly controlled by PP-InsPs, and that the human homolog of the yeast Pho84, GLUT2, contributes to inositol export. In summary, we discovered an evolutionarily conserved crosstalk pathway linking PP-InsPs to both phosphate and inositol homeostasis.
    DOI:  https://doi.org/10.1038/s44318-026-00888-9
  40. Exp Mol Med. 2026 Aug 07.
    Somatic mutations and genome mosaicism in aging and disease.
    Elizabeth Pan, Alexander Maslov, Jan Vijg.
      Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.
    DOI:  https://doi.org/10.1038/s12276-026-01791-3
  41. Genes Dev. 2026 Aug 06.
    Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes.
    Elisa Gomez-Gil, Paolo Guerra, Ying Gu, Sherman Foo, Benedicte Billard, Gabor Balogh, Maria Peter, Snezhana Oliferenko.
      The physicochemical properties of biological membranes must be maintained within a range compatible with cellular physiology. In the face of external perturbations, membrane lipid homeostasis mechanisms sense and control membrane features. How such mechanisms evolve to function in organisms with different cellular lipid make-up is unknown. Here, we address this fundamental question by exploiting the natural divergence in membrane lipid composition between the related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus Using lipidomics and transcriptomics, we show that the activity of the membrane-bound transcriptional activator Mga2, which regulates the Δ-9 desaturase Ole1 expression, is set to sense distinct levels of membrane unsaturation in the two species. Through retroengineering and physiological experiments, we identified an evolutionary divergent but functionally constrained element within the juxtamembrane region of Mga2, which fine-tunes its performance to species-specific lipid composition. Our experiments indicate that high baseline expression of ole1, set by cis-regulatory elements in its upstream noncoding region, has redefined the dynamic range of Mga2 activation in S. pombe, supporting high lipidome unsaturation. Our work explores an "experiment of nature" to highlight the broad principles underlying the organization and evolution of membrane homeostasis, which should be applicable to other genetic networks supporting cellular homeostatic processes.
    Keywords:  evolution; fission yeasts; homeostasis; membrane
    DOI:  https://doi.org/10.1101/gad.353500.125
  42. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  43. Nat Cell Biol. 2026 Aug 06.
    Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.
      
    DOI:  https://doi.org/10.1038/s41556-026-02032-5
  44. Mol Cell Biochem. 2026 Aug 07.
    Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
    Paulo Roberto Dos Santos, Joseph Rastegar, Mariana Roesch-Ely.
      Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.
    Keywords:  Coenzyme Q; Hydroxyhydroquinone; Metabolism; Mitochondrial; Ubiquinone
    DOI:  https://doi.org/10.1007/s11010-026-05687-8
  45. Nature. 2026 Aug 05.
    A compendium of next-generation patient-derived models for diverse cancers.
    HCMI Network
      The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.
    DOI:  https://doi.org/10.1038/s41586-026-10806-y
  46. Nat Aging. 2026 Aug 06.
    Social inequalities linked to accelerated biological aging.
    Susan Rahimi.
      
    DOI:  https://doi.org/10.1038/s43587-026-01201-3
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