bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–08–16
27 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Polyamines buffer labile iron to suppress ferroptosis.
  2. Stress granules confer an early vulnerability in KRAS-driven pancreatic tumorigenesis.
  3. An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
  4. Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
  5. p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
  6. Cell surface remodeling caused by the loss of the flippase subunit TMEM30A in immune cells.
  7. Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
  8. A new phase in KRAS signaling.
  9. The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026.
  10. Histological aging signatures for monitoring tissue-specific aging and disease.
  11. Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
  12. Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.
  13. Metabolic Labeling of Phosphatidylethanolamine Lipids in Cells Using Clickable Ethanolamine Analogs.
  14. Precision targeting of stromal states in pancreatic cancer: a clinical perspective.
  15. 7-Dehydrocholesterol-mediated ferroptosis is governed by glucose availability in pancreatic ductal adenocarcinoma.
  16. Targeting PRMT5 inhibitor-induced adaptation in pancreatic cancer with the RBM39 degrader indisulam.
  17. Impact of sphingomyelin species with different acyl chain lengths on plasma membrane organization.
  18. An iron logic unites bacterial and cancer persister cells.
  19. Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.
  20. Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
  21. Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
  22. In vivo genome-wide CRISPR screens of human T cells in solid tumours.
  23. FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
  24. High-throughput deformability-based microfluidic sorting reveals metastatic cancer subpopulations.
  25. Multifrequency magnetic resonance elastography for predicting pancreatic cancer aggressiveness and patient survival.
  26. Latent tumor killers awakened.
  27. Luminescent-reaction-enabled super-resolution imaging.
  1. Cell. 2026 Aug 14. pii: S0092-8674(26)00872-X. [Epub ahead of print]
    Polyamines buffer labile iron to suppress ferroptosis.
    Pushkal Sharma, Heather R Keys, Ryan P Mansell, Jillian Stark, Louisa Girard, Christalyn Ausler, Rachel Anderson, Sebastian Müller, Shinya Imada, Ivan S Pires, Tenzin Kunchok, Millenia Waite, Bingbing Yuan, Amy Deik, Luke Ferro, Paula T Hammond, Raphaël Rodriguez, Maria-Eirini Pandelia, Whitney S Henry, Ankur Jain.
      Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
    Keywords:  GPX4; ferroptosis; genetically encoded iron sensor; iron homeostasis; labile iron pool; polyamines; redox-active iron; spermidine; spermine
    DOI:  https://doi.org/10.1016/j.cell.2026.07.040
  2. Cell Rep. 2026 Aug 10. pii: S2211-1247(26)00907-1. [Epub ahead of print]45(8): 117829
    Stress granules confer an early vulnerability in KRAS-driven pancreatic tumorigenesis.
    Matias Estaras, Emma Cosialls, Gareth Pollin, Anass Berkachi, Noriyuki Nishiwaki, Gerardo Blanco, Miguel Fernandez-Bermejo, Antonio Gonzalez, Anil K Rustgi, Gwen Lomberk, Raul Urrutia, Patricia Santofimia-Castaño, Juan Iovanna.
      Pancreatic ductal adenocarcinoma (PDAC) is initiated by activating KRAS mutations, yet most pancreatic cells fail to survive the induced oncogenic stress. How a subset adapts to and initiates malignant transformation remains unclear. Here, we show that stress granules (SGs) formation is a key adaptive mechanism enabling these cells to tolerate oncogenic KRAS signaling. Although we determine that SGs are a generic response in stressed acinar cells, they are required for KRAS-mutant cells to progress to the preneoplastic stage. SGs blocking prevents KRAS-driven acinar-to-ductal metaplasia ex vivo and suppresses preneoplastic lesion formation in vivo. Importantly, SGs inhibition does not affect pancreatic damage during chronic pancreatitis, supporting its safety for selectively targeting KRAS-mutant cells. Finally, SGs are detected in pancreatic tissue from patients with chronic pancreatitis, confirming clinical relevance. Together, these findings identify SGs as a stress adaptation mechanism enabling tumor initiation and highlight them as a target for cancer interception in KRAS-driven PDACs.
    Keywords:  ADM; CP: cancer; mutant KRAS; pancreatic cancer; stress granules; transformation; tumor initiation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117829
  3. Autophagy. 2026 Aug 13. 1-11
    An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
    Dale P Corkery, Yao-Wen Wu.
      Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death. Recent advances identify membrane ATG8 conjugation (atg8ylation) as a key process that links damage detection to coordinated lysosomal repair, removal, and regeneration. Beyond its canonical role in macroautophagy, membrane atg8ylation also occurs on preexisting, non-autophagosomal single membranes through Conjugation of ATG8s to Single Membranes (CASM), positioning this pathway as a rapid response to membrane stress. Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling. These ligases convert damage signals into spatially restricted membrane atg8ylation, generating a membrane-associated platform that coordinates multiple downstream pathways. These include ESCRT-dependent membrane repair, ER-lysosome lipid transfer, membrane tubulation, and stress granule formation. When repair fails, membrane atg8ylation regulates lysophagy and activates lysosomal biogenesis and regeneration to restore lysosomal homeostasis. These emerging findings define membrane atg8ylation as a central organizer of membrane quality control rather than a pathway merely confined to macroautophagy. In this review, we summarize the current understanding of how membrane atg8ylation detects lysosomal damage and how this pathway coordinates other lysosomal quality control mechanisms to maintain lysosomal integrity.
    Keywords:  CASM; Lysosome; lysosomal membrane integrity; membrane atg8ylation; noncanonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2704442
  4. Nat Med. 2026 Aug;32(8): 2865-2877
    Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
    Ida Aronchik, Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick Pui Lai, Vidya Seshadri, Yu Chi Yang, Ashenafi Bulle, Marie Menard, Biswadeep Nayak, Mark P Labrecque, Julien Dilly, Eejung Kim, Lingyan Jiang, Jason Yano, Urszula N Wasko, Ciara Helland, Sean Bredeson, Brett Garrick, Yevgeniy Gindin, Brad Sickler, Xing Wei, Kyle Seamon, Jingjing Jiang, Kian-Huat Lim, Matthew Holderfield, Elsa Quintana, Aparna Hegde, Zeena Salman, Alexander Starodub, Alexander Spira, Wungki Park, David S Hong, Minal Barve, Meredith Pelster, David Sommerhalder, Salman R Punekar, Ignacio Garrido-Laguna, Brian M Wolpin, Anirban Maitra, W Clay Gustafson, Steve Kelsey, Jacqueline A M Smith, Kevin K Lin, Andrew J Aguirre, Mallika Singh.
      Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.
    DOI:  https://doi.org/10.1038/s41591-026-04537-w
  5. FEBS J. 2026 Aug 11.
    p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
    Jun-Ichi Sakamaki, Masaaki Komatsu.
      Upon exposure to stress, cells activate a variety of stress-response and quality-control mechanisms to maintain homeostasis. Dysregulation of these processes is implicated in numerous diseases, including cancer, liver disorders, and neurodegenerative diseases. p62/Sequestosome 1 (SQSTM1) is a multifunctional protein that plays a central role in protein homeostasis and stress responses by regulating autophagy and signal transduction pathways. Through its multiple protein-interacting domains, p62 functions both as a scaffold for selective autophagic degradation and as a signaling hub. Since our previous review of p62 a decade ago, substantial progress has been made in elucidating its molecular functions and physiological roles. Notably, p62 undergoes liquid-liquid phase separation with ubiquitinated proteins to form membraneless condensates, termed p62 bodies, when cells are exposed to proteotoxic stress. By sequestering specific proteins, p62 bodies act as platforms for autophagy-dependent degradation and stress signaling. These findings have substantially revised our view of p62 function, which was previously considered primarily as a receptor simply linking ubiquitinated substrates to autophagic membranes and connecting signaling molecules. This conceptual shift from one-to-one molecular interactions to multivalent, multimolecular, higher-order assemblies has fundamentally redefined the functional landscape of p62. In this review, we highlight how p62 bodies integrate selective autophagy and stress signaling, with a particular emphasis on their emerging roles in disease pathogenesis and their potential as therapeutic targets.
    Keywords:  KEAP1‐NRF2 pathway; liquid–liquid phase separation; p62 body; p62/SQSTM1; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1111/febs.70689
  6. J Cell Sci. 2026 Nov 01. pii: jcs264813. [Epub ahead of print]139(21):
    Cell surface remodeling caused by the loss of the flippase subunit TMEM30A in immune cells.
    Cenk O Gurdap, Franziska Ragaller, Marion Muller, Ellen Sjule, Taras Sych, Linnea Blomén, Fredrik B Thorén, Ilya Levental, Kandice R Levental, Quentin J Sattentau, Erdinc Sezgin.
      Plasma membrane lipid asymmetry is tightly regulated and fundamental to mammalian cell physiology. TMEM30A is the β-subunit of P4-ATPases, flippase enzymes that maintain strict phosphatidylserine (PS) asymmetry by pumping it from the outer to the cytosolic leaflet. Loss of TMEM30A function causes constitutive PS externalization and has been implicated in diseases such as diffuse large B-cell lymphoma and tumor immune evasion. Here, we systematically define the biophysical and molecular consequences of TMEM30A deletion in immune cells. Using a live-cell lipid reporter, membrane order probe, and surface proteome mapping, we show that TMEM30A-knockout cells display robust PS externalization accompanied by faster lateral diffusion of membrane constituents and decreased plasma membrane order. Surface proteome reorganization includes increased abundance of tetraspanins and CD47. Furthermore, TMEM30A loss triggers glycocalyx remodeling via ADAM10-dependent shedding, which removes major transmembrane mucins, including CD43 and CD162 (also known as SPN and SELPLG, respectively). Together, these data reveal a coordinated reorganization of lipids, glycans and proteins upon TMEM30A loss, suggesting mechanistic links between flippase dysfunction and increased plasma membrane dynamics and potential sensitization to immune therapy. Furthermore, our study provides an integrated surfaceome framework that might shed light on the relationship between TMEM30A expression and clinical outcomes in cancer.
    Keywords:  ADAM10; CD162; CD43; CD47; CDC50A; Immune evasion; Lipid asymmetry; Membrane order; Mucin shedding; Phosphatidylserine
    DOI:  https://doi.org/10.1242/jcs.264813
  7. FEBS Lett. 2026 Aug 10.
    Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
    Rainer Ettelt, Ana-Maria Sandru, Georg Vucak, Sebastian Didusch, Biljana Riemelmoser, Karin Ehrenreiter, Markus Hartl, Lukas A Huber, Manuela Baccarini.
      Lysosomes are dynamic organelles regulating metabolic signaling by recruiting cytosolic molecules to protein platforms on their limiting membrane. We used proximity labeling to define interactors and vicinal proteins of LAMTOR3, a component of the Ragulator scaffold that controls mTORC1 signaling and lysosome positioning. The screen has yielded several previously unappreciated interactors, including an actin remodeling network. Here, we characterize the RhoGEF PLEKHG3 as a LAMTOR3 vicinal protein colocalizing with peripheral lysosomes and cortical F-actin at focal adhesion sites. Forced peripheral dispersion of lysosomes drives PLEKHG3 accumulation at focal adhesions and decreases protrusive activity in both wild-type and PLEKHG3-deficient cells. Thus, lysosome positioning governs both PLEKHG3 localization and protrusive activity, yet the protrusion changes can occur independently of PLEKHG3.
    Keywords:  LAMTOR; PLEKHG3; cell motility; cytoskeleton; focal adhesions; lysosomes
    DOI:  https://doi.org/10.1002/1873-3468.70428
  8. Trends Cancer. 2026 Aug 10. pii: S2405-8033(26)00163-9. [Epub ahead of print]
    A new phase in KRAS signaling.
    Krista A Budinich, Liling Wan.
      By positioning phase separation between Kirsten rat sarcoma virus oncogene homolog (KRAS) lipidation and membrane signaling, Wang et al. unify distinct aspects of KRAS biology. They show that farnesylation drives cytoplasmic KRAS condensates that promote processing, trafficking, and signaling, establishing condensat formation as a new mechanism for controlling RAS activity.
    Keywords:  KRAS; biomolecular condensates; cancer; farnesylation; phase separation
    DOI:  https://doi.org/10.1016/j.trecan.2026.07.007
  9. J Hematol Oncol. 2026 Aug 08. pii: 53. [Epub ahead of print]19(1):
    The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026.
    Serena Pillozzi, Elisa Giommoni, Giulia Petroni, Daniele Rossini, Daniele Lavacchi, Marco Brugia, Andrea Galli, Lorenzo Antonuzzo.
      Survival in metastatic pancreatic ductal adenocarcinoma (mPDAC) has long been limited by a dismal second-line therapeutic ceiling dictated by conventional chemotherapy. However, breakthrough data from the ASCO 2026 Annual Meeting and the publication of the phase III RASolute-302 trial mark a definitive shift toward targeted KRAS inhibition. This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care. Concurrently, we evaluate emerging allele-specific strategies from ASCO 2026 designed to optimize target engagement and safety. These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into a manageable molecular entity.
    DOI:  https://doi.org/10.1186/s13045-026-01834-2
  10. Nat Med. 2026 Aug 14.
    Histological aging signatures for monitoring tissue-specific aging and disease.
    Ernesto Abila, Iva Buljan, Yimin Zheng, Lisa Kleissl, Sigrid Klotz, Tamas Veres, Zhilong Weng, Maja Nackenhorst, Rizqah Kamies, Anja Michl, Safwen Kadri, Samir Moustafa, Wolfgang Hulla, Matthias Perkonigg, Mathias Drach, Philipp Tschandl, Barbara Sterniczky, Matthias Heinig, Laurens J De Sadeleer, Wim Wuyts, Bart Vanaudenaerde, Laurens J Ceulemans, Daniel D Buchanan, Lochlan J Fennell, Georg Stary, Yuri Tolkach, Adelheid Wöhrer, Herbert B Schiller, André F Rendeiro.
      Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.
    DOI:  https://doi.org/10.1038/s41591-026-04566-5
  11. J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02302-1. [Epub ahead of print] 113430
    Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
    Johan Panek, Edward Fielder, Congsing Sun, Steph Crabtree, Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura Booth, Wyatt Yue, Gavin Richardson, Lauren Holder, Gavin J Miller, Jóhannes Reynisson, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.
    Keywords:  Autophagy; Mitophagy; Niemann-Pick type C1 disease; Oligomerisation; ROS; p62
    DOI:  https://doi.org/10.1016/j.jbc.2026.113430
  12. iScience. 2026 Aug 21. 29(8): 117071
    Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.
    Makoto Sano, Hideaki Ijichi, Sho Tabata, Akiyoshi Hirayama, Shuichi Shimma, Yohei Masugi, Yoshimi Ichimaru, Jinsuk Kim, Gen Kimura, Koji Miyabayashi, Ryota Takahashi, Hiroto Hatakeyama, Takahiro Suzuki, Atsushi Masamune, Tomoyoshi Soga, Mitsuhiro Fujishiro.
      Pancreatic ductal adenocarcinoma (PDAC) is the cancer with poorest prognosis, with metabolic reprogramming reported. We investigated metabolic alterations in mice with PDAC using capillary electrophoresis-mass spectrometry (CE-MS) and mass spectrometry imaging (MSI). o-Acetylcarnitine, a metabolite of carnitine, and acetyl-CoA increased during cancer progression in a PDAC mouse model by CE-MS, while MSI revealed that o-acetylcarnitine was mainly localized in PDAC cells. Also, immunohistochemistry showed overexpression of γ-butyrobetaine 2-oxoglutarate dioxygenase 1 (BBOX1), which synthesizes carnitine from γ-butyrobetaine, mainly in PDAC cells. Meldonium, an inhibitor of BBOX1, inhibited PDAC proliferation and cytokine secretion, thereby prolonging the survival of PDAC-bearing mice, accompanied by improved skeletal muscle atrophy. In patients undergoing PDAC resection, BBOX1 expression was determined as an independent poor prognostic factor for overall survival. Therefore, these results suggest that blocking L-carnitine synthesis would improve the prognosis of patients with PDAC.
    Keywords:  BBOX1; CE-MS; MSI; PDAC; cachexia; capillary electrophoresis-mass spectrometry; mass spectrometry imaging; meldonium; metabolome; o-acetylcarnitine; overall survival; pancreatic cancer; pancreatic ductal adenocarcinoma; γ-butyrobetaine 2-oxoglutarate dioxygenase 1
    DOI:  https://doi.org/10.1016/j.isci.2026.117071
  13. Chembiochem. 2026 Aug 14. 27(15): e70501
    Metabolic Labeling of Phosphatidylethanolamine Lipids in Cells Using Clickable Ethanolamine Analogs.
    Robert J Maraski, Jinchao Lou, Todd B Reynolds, Michael D Best.
      Phosphatidylethanolamine (PE) is the second most abundant phospholipid in mammalian cells. The cone-shaped structure of PE positions this lipid to act as a cornerstone of signaling events, such as those involving protein-protein and lipid-protein interactions, as it has been shown to promote conformational changes in both protein and lipid-based membrane structures. Despite this importance, chemical tools to interrogate the biological activity and trafficking of PE lipids are limited. Herein, we report the development of ethanolamine probes functionalized with clickable tags that are capable of infiltrating native cellular pathways and subsequently producing labeled PE lipids. Derivatization of click-tagged PE products enabled fluorescence microscopy imaging of these lipids in cells. Interrogation of the efficacy of these probes for biological incorporation was conducted using mass spectrometry and thin-layer chromatography analysis to identify various species of tagged PE molecules. This approach provides an invaluable step toward metabolic labeling strategies that will aid in the tracking of PE biosynthesis and trafficking pathways in cells.
    Keywords:  click chemistry; lipids; metabolic labeling; phosphatidylethanolamine
    DOI:  https://doi.org/10.1002/cbic.70501
  14. Trends Cancer. 2026 Aug 11. pii: S2405-8033(26)00159-7. [Epub ahead of print]
    Precision targeting of stromal states in pancreatic cancer: a clinical perspective.
    Anna Wolters, Maarten Bijlsma, Jai Prakash.
      Desmoplastic stroma defines pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. This stroma drives tumor progression, immune evasion, drug resistance, and poor drug delivery. Although targeting tumor stroma has shown preclinical promise, most clinical trials have failed due to limited translational success. A major hurdle is the stroma's extreme heterogeneity and dynamic nature, meaning uniform treatments fail. Emerging evidence supports the existence of distinct 'stromal states' with differential biological functions and therapeutic vulnerabilities. Characterizing these states provides a framework to stratify patients and guide precise, stroma-directed therapies. This review summarizes the clinical landscape of PDAC stroma-targeting strategies, discusses distinct stromal states, and outlines emerging opportunities to exploit the stroma as a therapeutic axis in PDAC to improve clinical trial outcomes.
    Keywords:  biomarkers; cancer-associated fibroblasts; extracellular matrix; nanomedicine; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.07.003
  15. Acta Biochim Biophys Sin (Shanghai). 2026 Aug 10.
    7-Dehydrocholesterol-mediated ferroptosis is governed by glucose availability in pancreatic ductal adenocarcinoma.
    Xiaojun Ren, Yaqiong Zhang, Xiaoxuan Zhou, Saijun Xiao, Kai Huang, Yingjie Dai, Xunjun Yang, Hezhi Fang, Jianxin Lyu, Zhengquan Yang, Minghua Jiang.
      7-Dehydrocholesterol (7-DHC) has recently emerged as an endogenous suppressor of lipid peroxidation/ferroptosis; however, its function in nutrient-poor microenvironments remains undefined. Here, we demonstrate that activated c-Myc directly occupies the DHCR7 promoter in pancreatic ductal adenocarcinoma (PDAC) cells, transcriptionally upregulating DHCR7, which converts 7-DHC into cholesterol, thereby fuelling PDAC cell proliferation. Under glucose deprivation, DHCR7 deletion triggers pronounced ferroptosis in PDAC cells, an effect that is sharply attenuated when glucose is supplemented. Mechanistically, DHCR7 inhibition drives 7-DHC accumulation, which plays a dual role: it traps free radicals (anti-ferroptosis) and yet simultaneously depletes the antioxidant pool (pro-ferroptosis), with the net outcome dictated by glucose availability. The antioxidant pool maintained by glucose is required to counteract the pro-peroxidation effects of 7-DHC; once glucose is limited, the radical-trapping-mediated anti-ferroptosis function of 7-DHC becomes negligible. Furthermore, glucose restriction in vitro and a low-glucose diet in vivo both sensitized PDAC cells to DHCR7 inhibition-triggered lipid peroxidation, which allows accelerated cell death or suppressed tumor growth. Collectively, 7-DHC, negatively regulated by the c-Myc/DHCR7 axis, promotes lipid peroxidation and ferroptosis in glucose-deficient PDAC tumors, revealing a metabolic vulnerability that can be exploited for therapy.
    Keywords:  7-dehydrocholesterol; glucose-deficient; lipid peroxidation; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3724/abbs.2026106
  16. Cancer Res Commun. 2026 Aug 12.
    Targeting PRMT5 inhibitor-induced adaptation in pancreatic cancer with the RBM39 degrader indisulam.
    Valentina Spielmann, Jonas Buchloh, Selen Selcen, Carolin Schneider, Shaishavi Jansari, Xin Fang, Ningjun Duan, Engin Demirdizen, Lukas Krauß, Jessica Eggert, Geraldine Siegfried, Sandrine Fedou, Christof Lenz, Lena Wieland, Lena-Christin Conradi, Maximilian Reichert, Volker Ellenrieder, Michael Ghadimi, Marian Grade, Elisabeth Hessmann, Abdel-Majid Khatib, Christian J Braun, Florian Wegwitz, Dieter Saur, Matthias Wirth, Günter Schneider.
      Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with co-deletion of the tumor suppressor CDKN2A and the methylthioadenosine phosphorylase (MTAP) gene, but resistance limits their efficacy. Our study suggests that compensatory spliceosomal reprogramming contributes to adaptation to PRMT5 inhibition. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). We investigated whether this response could be therapeutically leveraged by combining PRMT5 inhibition with Indisulam-mediated RBM39 degradation, which yielded synergistic activity in cellular model systems. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared to single-agent treatments. Multi-omics analysis revealed concomitant suppression of DNA repair and metabolic pathways. Collectively, our work support spliceosomal rewiring as a candidate adaptive response to PRMT5 inhibition and nominates RBM39 as a candidate therapeutic vulnerability, thereby supporting further evaluation of dual targeting of the splicing machinery.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0670
  17. Biochimie. 2026 Aug 10. pii: S0300-9084(26)00190-2. [Epub ahead of print]
    Impact of sphingomyelin species with different acyl chain lengths on plasma membrane organization.
    Nario Tomishige.
      The plasma membrane (PM) is characterized by asymmetric bilayer organization in terms of both the chemistry of lipid headgroups and the physical properties of lipid acyl chains. Sphingomyelin (SM), a major outer-leaflet lipid, has long been considered a key partner of cholesterol (Chol) in the formation of ordered membrane domains. However, mammalian cells contain multiple SM species with distinct N-acyl chains, most predominantly C16:0, C24:0, and C24:1, whose structural differences can change membrane packing, Chol distribution, and interleaflet communication. Evidence from model membranes shows that C16:0 SM interacts strongly with Chol and promotes liquid-ordered domain formation. By contrast, C24:0 SM generates thicker, potentially interdigitated bilayers, supports ordered domains with altered Chol association, and may influence coupling between two leaflets. C24:1 SM combines a very-long acyl chain with unsaturation, weakening membrane packing and suppressing macroscopic phase separation in Chol-containing membranes. Asymmetric vesicle studies further indicate that C24 SM can affect Chol transbilayer partitioning, which could have consequences for Chol accessibility and homeostatic signaling. Cellular studies further indicate that remodeling SM species can alter glycosylphosphatidylinositol (GPI)-anchored protein clustering, PM order, Chol-binding probe accessibility, and signaling proteins such as the insulin receptor. Together, current evidence supports a model in which SM species diversity tunes PM organization through coupled effects on lipid packing, Chol behavior, leaflet asymmetry, and protein function. Understanding these mechanisms in living cells remains an important issue for future studies.
    Keywords:  Acyl-chain diversity; Cholesterol; Microdomains; Plasma membrane; Sphingomyelin
    DOI:  https://doi.org/10.1016/j.biochi.2026.08.004
  18. Nat Rev Mol Cell Biol. 2026 Aug 11.
    An iron logic unites bacterial and cancer persister cells.
    Raphaël Rodriguez, Patrizia Agostinis.
      
    DOI:  https://doi.org/10.1038/s41580-026-01010-x
  19. Cell. 2026 Aug 04. pii: S0092-8674(26)00826-3. [Epub ahead of print]
    Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.
    YaTing Wen, LingJie Tang, WenWen Duan, QingFei Ren, YangYue Ni, ShiYang Chen, Jun Chen, Lei Yang, Huan Wang, Yuan Chen, YunZhe Zheng, XingChao Pan, Hui Du, MengWen Huang, An Zeng, Zhaocai Zhou, ZhiGang Zhang, HongBin Ji, GaoXiang Ge, Yi Arial Zeng, Wei Zhang, ShiHui Wang, JianJun Cheng, Sheng Wang, JianFeng Chen.
      Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8+ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT2AR agonists as a therapeutic strategy for CRC immunotherapy.
    Keywords:  5-HT(2A)R agonist; colorectal cancer; cytotoxic CD8(+) T cell; enteric glial cell
    DOI:  https://doi.org/10.1016/j.cell.2026.07.028
  20. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2610420123
    Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain PM integrity to prevent cell death. Genetic loss of PM repair factors is associated with human diseases such as muscular dystrophy. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage remains unclear. Here, leveraging quantitative organellar proteomics and genome-wide CRISPR interference screens, we identify sorcin as a PM repair factor that couples annexin A11 (ANXA11)-mediated sensing of PM damage to ESCRT-III assembly. We show that sorcin directly binds ANXA11 and ALIX in the presence of Ca2+ via its penta-EF-hand domain and flexible N terminus, respectively, and is required for ESCRT-III recruitment to PM lesions and membrane resealing. Our data support a model in which ANXA11, recruited to the PM upon damage-induced Ca2+ influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Together, these findings establish a Ca2+-dependent scaffolding mechanism that couples PM damage sensing to ESCRT-III assembly for PM repair.
    Keywords:  annexin; endosomal sorting complex required for transport (ESCRT); membrane repair; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2610420123
  21. EMBO Rep. 2026 Aug 14.
    Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
    Guillermo Puertas-Frías, María José Saucedo-Rodríguez, Kristýna Čunátová, Lukáš Alán, Patrik Hrbáč, Michal Knězů, Soňa Koníčková, Jakub Schimmer, Monika Krakovková, Marek Vrbacký, Tomáš Čajka, Ondřej Kuda, Erika Fernández-Vizarra, Massimo Zeviani, Hana Hansíková, Tomáš Honzík, Josef Houštěk, Petr Pecina, Tomáš Mráček, Alena Pecinová.
      Impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects. However, secondary metabolic disturbances also represent an important trigger for pathologies originating from OXPHOS aberrations. Here we show that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). We demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in cells under hypoxia and in immortalised fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As a proof of principle, we observe elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.
    DOI:  https://doi.org/10.1038/s44319-026-00898-y
  22. Nature. 2026 Aug 12.
    In vivo genome-wide CRISPR screens of human T cells in solid tumours.
    Qi Liu, Peixin Amy Chen, Esha Urs, Shimin Zhang, Maya M Arce, Charlotte H Wang, Jun Yan, Vinh Q Nguyen, Zhongmei Li, Jin Seo, Nupura Kale, Fanglue Peng, Yikai Luo, Laine Goudy, Taylor N LaFlam, Haixia Zhong, Chandrima Modak, Emma Dann, Jae Hyung Jung, Amanda Kirane, Allison Betof Warner, Boi Bryant Quach, Zinaida Good, Brian R Shy, Eric Shifrut, Sagar P Bapat, Greg M Allen, Justin Eyquem, Katherine Fuh, Stacie E Dodgson, Jason G Cyster, Alexander Marson, Julia Carnevale.
      Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro1,2. In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.
    DOI:  https://doi.org/10.1038/s41586-026-10906-9
  23. Autophagy Rep. 2026 ;5(1): 2705631
    FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
    Halvor Ullern, Julie Aarmo Johannessen, Feyza Kasikci, Miriam Formica, Naghmeh Karimi Melve, Siri Andresen, Andreas Brech, Karol Axcrona, Kjersti Jørgensen, Lorant Farkas, Jorrit M Enserink, Helene Knævelsrud.
      Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation were unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate aberrant p62 accumulation in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate that FLCN loss is characterized by SQSTM1/p62 accumulation, although SQSTM1/p62 appears dispensable for anchorage-independent growth in cell models.
    Keywords:  Autophagy; BHD; FLCN; SQSTM1/p62; renal cell carcinoma
    DOI:  https://doi.org/10.1080/27694127.2026.2705631
  24. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2604094123
    High-throughput deformability-based microfluidic sorting reveals metastatic cancer subpopulations.
    Xiaoyan Liu, Yuanchao Liu, Junwei Li, Zhibei Wang, Mui Hoon Brenda Nai, Qian Chen, Haodong Li, Xingyu Jiang, Shaofei Shen, Chwee Teck Lim.
      The deformability of cancer cells is a critical indicator of their malignancy, as this mechanical property of cancer cells can reflect various biostructural and biochemical changes such as the cytoskeletons and protein expressions. However, selectively isolating and analyzing cell subpopulations with differing deformability and their associated biological properties remains challenging, especially at high throughput. Here, we introduce a microstructure-assisted spiral microfluidic platform that sorts cancer cells based on their deformability at ultrahigh throughput (>2,000,000 cells min-1) and couples the workflow to real-time, image-based phenotyping of cell parameters. We profile the sorted fractions and investigate a tripartite correlation between the deformability of cancer cells, the expression of proteins in different subpopulations, and the metastatic ability of cancer cells. This tripartite correlation has been confirmed in human breast cancer cell lines with metastatic potential (including MDA-MB-231 cells and BT-549 cells), where these cells are classified into subpopulations based on their deformability. The more deformable subpopulation exhibits increased invasiveness and distinct cytoskeletal remodeling and epithelial-to-mesenchymal transition (EMT)-associated protein signatures. Leveraging these deformability differences, our label-free platform enables high-throughput enrichment of aggressive cancer subpopulations and provides a scalable front end for liquid biopsy workflows. More broadly, deformability-based sorting may support improved analysis of rare metastasis-prone cells and accelerate high-throughput screening for mechano-targeted therapeutic strategies, offering a practical route to integrate cell deformability into precision oncology and therapy.
    Keywords:  cancer cell deformability; high-throughput screening; lab-on-a-chip; microfluidic sorting
    DOI:  https://doi.org/10.1073/pnas.2604094123
  25. Eur Radiol. 2026 Aug 14.
    Multifrequency magnetic resonance elastography for predicting pancreatic cancer aggressiveness and patient survival.
    Qi Wang, Jingyi Liu, Menghua Dai, Liang Zhu, Xuan Wang, Bowen Wu, Jing Guo, Ingolf Sack, Feng Feng.
       OBJECTIVES: To evaluate the spatial heterogeneity of viscoelastic properties in pancreatic cancer, to correlate MR elastography (MRE) parameters with clinicopathological factors indicating tumor aggressiveness, and to identify risk factors for patient survival.
    MATERIALS AND METHODS: This retrospective study included 96 treatment-naive pancreatic cancer patients undergoing multifrequency MRE between September 2018 and May 2024. High-resolution parametric maps were generated to measure stiffness and fluidity in central, peripheral, and whole-tumor regions. Correlations between MRE parameters and tumor stage, grade, vascular and perineural invasion, regional lymphadenopathy, and distant metastasis were analyzed. Kaplan-Meier and Cox proportional hazards models were used to identify prognostic factors in patients with and without R0 resection, respectively.
    RESULTS: Peripheral fluidity of the tumor was higher than central fluidity (1.23 ± 0.25 vs 0.95 ± 0.19 rad, p < 0.001), whereas stiffness showed no zonal difference (p = 0.07). Tumor stiffness correlated positively with vascular invasion (ρ = 0.21, p = 0.04). Peripheral tumor fluidity correlated positively with tumor stage (ρ = 0.28, p = 0.007), perineural invasion (ρ = 0.31, p = 0.02), regional lymphadenopathy (ρ = 0.29, p = 0.005), and distant metastasis (ρ = 0.26, p = 0.01). In 48 R0-resected patients, higher peripheral fluidity was associated with shorter disease-free survival (DFS) (9.1 vs 19.4 months, p = 0.009) and was identified as an independent predictor of shorter DFS (hazard ratio, 2.15; 95% confidence interval: 1.03, 4.50; p = 0.04).
    CONCLUSION: Tumor biomechanical properties quantified by in vivo multifrequency MRE predict pancreatic cancer aggressiveness and patient survival.
    KEY POINTS: Question Pretreatment identification of aggressive pancreatic cancer remains challenging. Non-invasive imaging biomarkers are needed to stratify patient risk and optimize individualized treatment strategies. Findings Peripheral tumor fluidity quantified by multifrequency MRE correlates with pancreatic cancer aggressiveness and independently predicts DFS in patients with R0-resected pancreatic cancer. Clinical relevance MRE-derived peripheral fluidity provides a biophysical marker for pancreatic cancer aggressiveness. This facilitates risk stratification and identifying high-risk candidates for targeted neoadjuvant therapy.
    Keywords:  Intratumoral heterogeneity; Multifrequency magnetic resonance elastography; Pancreatic cancer; Survival; Tumor aggressiveness
    DOI:  https://doi.org/10.1007/s00330-026-12824-w
  26. Cancer Cell. 2026 Aug 10. pii: S1535-6108(26)00308-9. [Epub ahead of print]
    Latent tumor killers awakened.
    Haochen Yang, Chenqi Xu.
      In this issue of Cancer Cell, Kehl et al. construct a single-cell atlas of bone marrow T cells from patients with bone marrow-resident malignancies, identifying tumor-reactive populations existing in a state of latent competence. A 15-gene signature identifies this subset, which is expanded by immunotherapies and predicts clinical responses.
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.021
  27. Nature. 2026 Aug 12.
    Luminescent-reaction-enabled super-resolution imaging.
    Wenxin Zhu, Chi Zhang, Jiahui Gui, Yibo Yang, Yuxin Wan, Xin Wang, Liying Qu, Ao Guo, Ziqing Zhang, Zhenqian Han, Weisong Zhao, Jiandong Feng.
      By breaking the optical diffraction limit, super-resolution fluorescence microscopy has advanced our understanding of biological complexity under the framework of light-excited luminescence1. The use of external light excitation remains a key factor that shapes the imaging capabilities and live-cell compatibility of fluorescence-based approaches2. An alternative is the reaction-excited luminescence, such as electrochemiluminescence (ECL)3, chemiluminescence (CL)4 and bioluminescence (BL)5, providing a chemically defined toolbox for enabling different imaging merits, from ultrasensitive analysis6,7 to biocompatible imaging8,9. Despite its light-free excitation and high sensitivity, conventional luminescent-reaction-enabled imaging is fundamentally limited in spatiotemporal resolution owing to low photon budget10,11. Here we develop a chemistry-based super-resolution imaging framework, luminescent-reaction-enabled super-resolution imaging via entropy-weighted correlation combined with deconvolution (RIED). As an experimental-computational concept, RIED introduces a spatiotemporal recording strategy to uncover specific luminescent-reaction-enabled imaging information content, which is efficiently collected and computed to achieve super resolution using a reconstruction strategy adapted to reaction-driven photon statistics. We achieve super-resolution ECL, CL and BL imaging of intracellular organelles, attaining approximately 100 nm resolution. This approach is used for highly sensitive imaging of surface proteins and 41-h ultralong-term continuous super-resolution live-cell imaging of mitochondrial transfer dynamics. Our work establishes an emerging class of chemistry-enabled, laser-free super-resolution microscopy with expanded biological imaging versatilities.
    DOI:  https://doi.org/10.1038/s41586-026-10889-7
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