bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–10–05
forty-one papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.
  2. Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates.
  3. Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.
  4. Obstacles Regulate Membrane Tension Propagation to Enable Localized Mechanotransduction.
  5. Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth.
  6. Targeted Detection of Phospholipid Aldehydes in Living Cells by Oxime Ligation.
  7. The tumour microenvironment in pancreatic cancer - new clinical challenges, but more opportunities.
  8. From Worms to Tumors: Conserved Strategies of Cellular Arrest and Survival Governing Dormancy.
  9. Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking.
  10. Spatially resolving cancer: from cell states to therapy.
  11. Autophagy-dependent proteostasis suppresses breast cancer metastasis.
  12. Highly multiplexed 3D profiling of cell states and immune niches in human tumors.
  13. Personalizing Chemotherapy in Metastatic Pancreatic Cancer.
  14. Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.
  15. Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer.
  16. Cardiac lipid droplets differ under pathological and physiological conditions.
  17. Tissue Fluidity Mediates a Trade-off Between the Speed and Accuracy of Multicellular Patterning by Cell Sorting.
  18. Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
  19. Development of a new flippase-dependent mouse model for red fluorescence-based isolation of Kras G12D oncogene-expressing tumor cells.
  20. A needed nomenclature for nucleosomes.
  21. CRESTA: a comprehensive transcriptome atlas for cellular response to external stressors.
  22. Association between weight loss and overall survival in patients with pancreatic cancer: a meta-analysis.
  23. Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling.
  24. Aging: the wound that never starts healing.
  25. Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
  26. Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.
  27. Theory of Condensate Size Control by Molecular Charge Asymmetry.
  28. ApoCIII-induced hyperlipidemia alters lipid packing in erythrocyte membranes without affecting fluidity.
  29. A pathway that controls conversion of the amino acid cysteine into a cholesterol regulator.
  30. Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.
  31. Best practices and tools in R and Python for statistical processing and visualization of lipidomics and metabolomics data.
  32. Proteotoxic stress response drives T cell exhaustion and immune evasion.
  33. SurvBoard: standardized benchmarking for multi-omics cancer survival models.
  34. Co-occurring Mutations in Different Genes Can Fuel Oncogenic Signaling and Serve as Metastatic Tumor Markers.
  35. FRET-based biosensor moxCRONOS enables quantitative monitoring of macromolecular crowding in organelles and protein aggregates.
  36. A computational framework for the investigation of phosphoinositide regulation.
  37. Prevention of type 2 diabetes through prediabetes remission without weight loss.
  38. Lipidomic Sample Preparation to Detect Phosphatidylcholine Alterations in Skeletal Muscle.
  39. CellNavi predicts genes directing cellular transitions by learning a gene graph-enhanced cell state manifold.
  40. Pericyte-tumor crosstalk facilitates metastatic tumor cell latency through PIEZO1-activated lysophospholipid transfer.
  41. A ratiometric fluorescent probe monitoring lipid peroxidation within lipid droplets in foam cells.
  1. J Appl Physiol (1985). 2025 Sep 30.
    Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.
    Natalia M Weinzierl, Jayarani Putri, Kathryn M Spitler, Erin E Talbert.
      Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP) model, which utilizes an inducible Cre recombinase to initiate tumor development by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Given the expanding evidence of sexual dimorphisms in cancer cachexia, we utilized both male and female mice to assess potential sex differences. Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.
    Keywords:  Cachexia; development; mouse models; sexual dimorphism
    DOI:  https://doi.org/10.1152/japplphysiol.00706.2025
  2. Nat Commun. 2025 Sep 30. 16(1): 8696
    Engineered exosomes with KrasG12D specific siRNA in pancreatic cancer: a phase I study with immunological correlates.
    Valerie S Kalluri, Brandon G Smaglo, Krishnan K Mahadevan, Michelle L Kirtley, Kathleen M McAndrews, Mayela Mendt, Sujuan Yang, Ana S Maldonado, Hikaru Sugimoto, Maria E Salvatierra, Luisa M Solis Soto, Cara Haymaker, Rick Finch, Mihai Gagea, Adam C Fluty, Steven J Ludtke, J Jack Lee, Abhinav K Jain, Gauri Varadhachary, Rachna T Shroff, Anirban Maitra, Elizabeth Shpall, Shubham Pant, Raghu Kalluri.
      Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal a biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKrasG12D in the iEXPLORE (iExoKrasG12D in Pancreatic Cancer) Phase I study employed a non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKrasG12D therapy was well-tolerated: the primary outcomes were met with iExoKrasG12D showing no dose-limiting toxicity. The maximum tolerated dose was not reached even at the highest dose. In some cases, iExoKrasG12D therapy was associated with stable disease response (secondary outcome). Downregulation of KRASG12D DNA and suppression of phospho-Erk was documented together with an increase in intratumoral CD8+ T cells following treatment. The CD8+ T cell recruitment priming by iExoKrasG12D informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKrasG12D and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust pre-clinical anti-tumor efficacy via FAS mediated CD8+ T cell anti-tumor activity. This first-in-human, precision medicine clinical trial and supporting preclinical functional studies offer new insights into priming of immunotherapy by oncogenic Kras inhibitor for future opportunistic combination therapy for PDAC patients.
    DOI:  https://doi.org/10.1038/s41467-025-63718-2
  3. Brain Behav Immun. 2025 Sep 27. pii: S0889-1591(25)00365-4. [Epub ahead of print] 106123
    Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.
    Kyna Conn, Laura Milton, Alyssa Teoh, Priscila T Levi, Kelly L Walton, Zane B Andrews, Claire J Foldi, Sarah H Lockie.
      Approximately 50-80 % of cancer patients suffer from cachexia, a metabolic syndrome involving inflammation, appetite loss, and muscle and fat wasting. Another common co-morbidity of cancer patients is cognitive impairment, and clinical evidence suggests the incidence of cachexia is linked to more severe cognitive symptoms. Given the difficulty of studying changes in cognitive function in human cancer patients, we set out to examine key aspects of cognitive performance in a mouse model of pancreatic cancer (pancreatic ductal adenocarcinoma; PDAC) cachexia, using an in-cage operant device (Feeding Experimental Device version 3; FED3) and a reversal learning task. Performance on the operant reversal task was compared to two control groups without cancer: ad libitum fed, sham injected with phosphate buffered saline (PBS), calorie restricted (CR) to 90-95 % of original body weight to control for reduced food intake and weight loss in cachexia mice. Our PDAC model recapitulated features of cachexia, including anorexia, weight loss, muscle wastage and inflammation. CR mice performed significantly better on the reversal task than both PDAC and PBS mice, achieving significantly more reversals and greater pellet retrieval. There was no difference between PBS and PDAC groups. These results suggest that the weight and appetite loss that occurs during cancer is processed by the brain differently to weight loss that occurs as a result of calorie restriction, with PDAC mice not experiencing an increase in motivational drive for food in line with their falling body weight. To mimic the malaise experienced by the PDAC group, we dosed CR mice with LiCl. Low dose (150 mM) LiCl did not affect responding, however, high dose (300 mM) LiCl significantly reduced both number of active pokes and pellet retrieval. This indicates a sickness-induced devaluation of reward, a factor that may impact poor performance of this task in the PDAC group. We additionally examined exploratory and anxiety-like behaviour in PBS and PDAC groups using a battery of maze-based tests. We saw no significant differences in performance between groups in the elevated plus maze, open field or light/dark box, suggesting no elevations in baseline anxiety-like symptoms in this cachexia model. These results occurred in the face of significantly elevated levels of the pro-cachexia factors GDF15, Activin A and Activin B, indicating that elevated levels of these TGF-β family peptides are not sufficient to produce behavioural changes in these tests. Our results provide evidence for a specific impact of sickness state on cognitive flexibility during pancreatic cancer.
    Keywords:  Behaviour; Cancer cachexia; Cognitive flexibility; Instrumental learning; LiCl; Malaise; Mouse model; Reversal learning
    DOI:  https://doi.org/10.1016/j.bbi.2025.106123
  4. bioRxiv. 2025 Sep 23. pii: 2025.01.14.632796. [Epub ahead of print]
    Obstacles Regulate Membrane Tension Propagation to Enable Localized Mechanotransduction.
    Frederic Català-Castro, Mayte Bonilla-Quintana, Neus Sanfeliu-Cerdán, Padmini Rangamani, Michael Krieg.
      Forces applied to cellular membranes lead to transient membrane tension gradients. The way membrane tension propagates away from the stimulus site into the membrane reservoir is a key property in cellular adaptation. However, it remains unclear how tension propagation in membranes is regulated and how it depends on the cell type. Here, we investigate plasma membrane tension propagation in cultured Caenorhabditis elegans mechanosensory neurons. We show that tension propagation travels quickly and is restricted to a particular distance in the neurites - projections from the cell body of a neuron. A biophysical model of tension propagation suggests that periodic obstacle density and arrangement play key roles in controlling the propagation of mechanical information. Our experiments show that tension propagation is strongly dependent on the intact actin and microtubule cytoskeleton, whereas membrane lipid properties have minimal impact. In particular, the organization of the α/β -spectrin network and the MEC-2 stomatin condensates in periodic scaffold act as barriers to tension propagation, limiting the spread of tension. Our findings suggest that restricting membrane tension propagation in space and time enables precise localized signaling, allows a single neuron to process mechanical signals in multiple distinct domains, thus expanding its computational capacity.
    DOI:  https://doi.org/10.1101/2025.01.14.632796
  5. Cancer Discov. 2025 Sep 30. OF1-OF30
    Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth.
    Surajit Sinha, Abir Kumar Panda, Rodrigo Xavier das Neves, Zeribe C Nwosu, Ke Xu, Elke van Beek, Priyanka P Desai, Sivasish Sindiri, Sruthi Chempati, Kirsten Remmert, Billel Gasmi, Linda Bojmar, Constantinos Zambirinis, Alexander J Rossi, Reed I Ayabe, Michael M Wach, James D McDonald, Samantha M Ruff, Emily A Verbus, Areeba Saif, Alyssa V Eade, Carolina M Larrain, Lindsay R Friedman, Shreya Gupta, Alok Ranjan, Martha E Teke, Tahsin M Khan, Tracey Pu, Amber Leila Sarvestani, Carrie E Ryan, Jacob T Lambdin, Kenneth Luberice, Stephanie N Gregory, Stephanie C Lux, Hanna Hong, Allen J Luna, Imani A Alexander, Sarfraz R Akmal, Shahyan U Rehman, Ashley Rainey, Todd D Prickett, Vishal N Koparde, Samantha Sevilla, Skyler A Kuhn, King Chan, Zhonghe Sun, Nina Bubunenko, Eileen Li, Cathleen Hannah, Geneti Gaga, Thorkell Andresson, Margaret C Cam, Xiaolin Wu, Lisa M Jenkins, Andrew M Blakely, Jeremy L Davis, Giorgio Trinchieri, Pankaj K Singh, James C Yang, Marina Pasca di Magliano, Costas A Lyssiotis, Michael B Yaffe, Ethan M Shevach, Jonathan M Hernandez.
      Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells that identified the RNA-binding protein GCN1 as an integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside the activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules and NK ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade.
    SIGNIFICANCE: Metastatic tumor cells display profound immunometabolic plasticity to colonize distant organs. We identify IMPACT, an inhibitor of GCN1-stress signaling, expression of which curtailed metabolic plasticity and augmented tumor immunogenicity, sensitizing metastatic tumor cells to NK cell-mediated destruction.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1055
  6. Angew Chem Int Ed Engl. 2025 Oct 01. e202512578
    Targeted Detection of Phospholipid Aldehydes in Living Cells by Oxime Ligation.
    Jacob A Vance, Wei-An Chen, Palina Nepachalovich, Caroline Knittel, Maria Fedorova, Neal K Devaraj.
      Oxidatively damaged lipids play critical roles in numerous human pathologies, yet methods to directly identify these species within living cells remain limited due to their transient and low-abundance nature. Among lipid oxidation products, aldehyde-containing lipids are significant due to their heightened reactivity and strong links to disease pathology. Here, we introduce OxiLox (oxime ligation to oxidized lipids), a method that leverages fluorescent hydroxylamine-based probes to enable direct, chemoselective tagging of aldehyde-containing lipids within living cells via rapid oxime ligation. Using confocal microscopy, we observe the subcellular localization of these oxidized lipids, highlighting prominent accumulation within perinuclear membranes, particularly under oxidative stress conditions induced by the ferroptosis activator RSL3. Coupled with high-resolution mass spectrometry, our method identifies aldehyde lipid species, notably revealing the abundance of oxidized plasmenyl phosphatidylethanolamines in ferroptotic cells. We demonstrate that cellular labeling by hydroxylamine probes can be modulated by altering the expression of antioxidant enzymes such as aldose reductase (AKR1B1), underscoring the relationship between enzymatic antioxidant defenses and lipid aldehyde metabolism. Our work establishes OxiLox as a robust approach for direct, sensitive, and chemically precise detection of lipid aldehydes in live cells, offering new insights into the role of lipid oxidation in health and disease.
    Keywords:  Bioconjugation; Chemical biology; Ferroptosis; Lipid peroxidation; Membrane biochemistry
    DOI:  https://doi.org/10.1002/anie.202512578
  7. Nat Rev Clin Oncol. 2025 Oct 03.
    The tumour microenvironment in pancreatic cancer - new clinical challenges, but more opportunities.
    Heng-Chung Kung, Kevin W Zheng, Jacquelyn W Zimmerman, Lei Zheng.
      Patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) predominantly receive chemotherapy, and despite initial responses in some patients, most will have disease progression and often dismal outcomes. This lack of clinical effectiveness partly reflects not only cancer cell-intrinsic factors but also the presence of a tumour microenvironment (TME) that precludes access of both systemic therapies and circulating immune cells to the primary tumour, as well as supporting the growth of PDAC cells. Combined with improved preclinical models of PDAC, advances in single-cell spatial multi-omics and machine learning-based models have provided novel methods of untangling the complexities of the TME. In this Review, we focus on the desmoplastic stroma and both the intratumoural and intertumoural heterogeneity of PDAC, with an emphasis on cancer-associated fibroblasts and their surrounding immune cell niches. We describe new approaches in converting the immunologically 'cold' PDAC TME into a 'hot' TME by priming T cell activation, overcoming T cell exhaustion and unravelling myeloid cell-mediated immunosuppression. Furthermore, we explore integrated targets involving the TME, such as points of convergence among tumour, stromal and immune cell metabolism as well as oncogenic KRAS signalling. Finally, building on our experience with failed clinical trials in the past, we consider how this evolving comprehensive understanding of the TME will ensure future success in developing more effective therapies for patients with PDAC.
    DOI:  https://doi.org/10.1038/s41571-025-01077-z
  8. Cancer Res. 2025 Oct 03.
    From Worms to Tumors: Conserved Strategies of Cellular Arrest and Survival Governing Dormancy.
    Veena Prahlad, Irwin H Gelman.
      The recurrence of metastatic lesions months to years after the treatment of primary cancers remains a major contributor to cancer-related mortality, highlighting the need to better understand the mechanisms that govern dormancy and dormancy reawakening. A major hurdle is the lack of adequate in vitro and in vivo models to dissect the complex cascades that trigger tumor cell dissemination, adoption of the dormant state, or tumor cell outgrowth in the new metastatic microenvironmental niche. However, many organisms use dormancy to survive stressful environments or periods of nutrient deprivation. Of these, the dauer state of the free-living nematodes C. elegans has unparalleled characterization. Here, we discuss the remarkable physiological, signaling, genomic, and metabolic similarities between dormant cancer cells and C. elegans dauers, arguing for the use of dauers as a facile model to help dissect dormancy and reawakening pathways in cancer cells.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2050
  9. ACS Cent Sci. 2025 Sep 24. 11(9): 1736-1752
    Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking.
    Noemi Jiménez-Rojo, Suihan Feng, Johannes Morstein, Stefanie D Pritzl, Antonino Asaro, Sergio López, Yun Xu, Takeshi Harayama, Nynke A Vepřek, Christopher J Arp, Martin Reynders, Alexander J E Novak, Evgeny Kanshin, Jan Lipfert, Beatrix Ueberheide, Manuel Muñiz, Theobald Lohmüller, Howard Riezman, Dirk Trauner.
      The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical approach to manipulate membrane viscosity based on an exogenous synthetic fatty acid with an azobenzene photoswitch, termed FAAzo4. Cells rapidly incorporate FAAzo4 into phosphatidylcholine and phosphatidylethanolamine in a concentration- and cell type-dependent manner. This generates photoswitchable PC and PE analogs, which are predominantly located in the endoplasmic reticulum. Irradiation causes a rapid photoisomerization that decreases membrane viscosity with high spatiotemporal precision. We use the resulting "PhotoCells" to study the impact of membrane viscosity on ER-to-Golgi transport and demonstrate that this two-step process has distinct membrane viscosity requirements. Our approach provides an unprecedented way of manipulating membrane biophysical properties directly in living cells and opens novel avenues to probe the effects of viscosity in a wide variety of biological processes.
    DOI:  https://doi.org/10.1021/acscentsci.5c00606
  10. Trends Cancer. 2025 Oct 02. pii: S2405-8033(25)00230-4. [Epub ahead of print]
    Spatially resolving cancer: from cell states to therapy.
    Guangsheng Pei, Yang Liu, Linghua Wang.
      Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.
    Keywords:  cancer cell state; computational pathology; machine learning; multimodal data integration; spatial multi-omics; spatial profiling
    DOI:  https://doi.org/10.1016/j.trecan.2025.09.002
  11. Autophagy. 2025 Oct 02.
    Autophagy-dependent proteostasis suppresses breast cancer metastasis.
    Jayanta Debnath, Gourish Mondal.
      In breast cancer, macroautophagy/autophagy suppresses key steps of the metastatic cascade, including colonization and outgrowth at distant sites. However, the molecular mechanisms behind this suppression have remained unclear. Our recent study shows that increased metastasis observed in the setting of autophagy deficiency is driven by the accumulation of phase-separated biomolecular condensates containing the autophagy cargo receptors NBR1 and SQSTM1. These NBR1-SQSTM1 condensates sequester ITCH, an E3 ubiquitin ligase responsible for degrading TP63, a transcription factor that promotes basal differentiation. Hence, ITCH sequestration stabilizes and activates TP63 in breast cancer cells, hence promoting an aggressive, pro-metastatic basal-like differentiation state. Overall, our findings suggest that the potential benefits of targeting autophagy in cancer therapy are accompanied by defects in proteostasis, which disrupts epithelial lineage fidelity and enhances metastatic potential. We propose that targeting NBR1-SQSTM1 condensates may offer new therapeutic avenues to prevent metastasis, particularly in the context of autophagy deficiency.
    Keywords:  Autophagy; autophagy cargo receptors; biomolecular condensates; lineage infidelity; metastasis
    DOI:  https://doi.org/10.1080/15548627.2025.2569677
  12. Nat Methods. 2025 Sep 29.
    Highly multiplexed 3D profiling of cell states and immune niches in human tumors.
    Clarence Yapp, Ajit J Nirmal, Felix Zhou, Alex Y H Wong, Juliann B Tefft, Yi Daniel Lu, Zhiguo Shang, Zoltan Maliga, Paula Montero Llopis, George F Murphy, Christine G Lian, Gaudenz Danuser, Sandro Santagata, Peter K Sorger.
      Diseases such as cancer involve alterations in cell proportions, states and interactions, as well as complex changes in tissue morphology and architecture. Histopathological diagnosis of disease and most multiplexed spatial profiling relies on inspecting thin (4-5 µm) specimens. Here we describe a high-plex cyclic immunofluorescence method for three-dimensional tissue imaging and use it to show that few, if any, cells are intact in conventional thin tissue sections, reducing the accuracy of cell phenotyping and interaction analysis. However, three-dimensional cyclic immunofluorescence of sections eightfold to tenfold thicker enables accurate morphological assessment of diverse protein markers in intact tumor, immune and stromal cells. Moreover, the high resolution of this confocal approach generates images of cells in a preserved tissue environment at a level of detail previously limited to cell culture. Precise imaging of cell membranes also makes it possible to detect and map cell-cell contacts and juxtracrine signaling complexes in immune cell niches.
    DOI:  https://doi.org/10.1038/s41592-025-02824-x
  13. J Clin Oncol. 2025 Oct 01. JCO2501786
    Personalizing Chemotherapy in Metastatic Pancreatic Cancer.
    Thomas Seufferlein.
      
    DOI:  https://doi.org/10.1200/JCO-25-01786
  14. bioRxiv. 2025 Sep 23. pii: 2025.09.22.677807. [Epub ahead of print]
    Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.
    Michal J Nagiec, Paola M Cavaliere, Friederike Dundar, Derrick M Spencer, Nikolaos Koundouros, Joana B Nunes, Sejeong Shin, Sang-Oh Yoon, Julie Han, Andre Chavez, Olivia M Kester, Rabia Khan, Paul Zumbo, Eric E Gardner, Bobak Parang, Anders P Mutvei, John M Asara, Steven P Gygi, Doron Betel, Noah Dephoure, John Blenis.
      Metastatic cancer cells invade tissue, overcome nutrient stress, and survive transit to distant sites. Many of the mechanisms that support these processes are incompatible with proliferation. This study defines cellular transition states in breast epithelial cells undergoing epithelial-mesenchymal transition (EMT) driven by ERK2 and TGF-β signaling. EMT triggers robust endolysosomal system upregulation and metabolic adaptations that balance proliferative and invasive states. Surprisingly, invasive cells rely on scavenging via lysosomes and macropinocytosis to acquire amino acids, rather than plasma membrane transport, even in nutrient-rich conditions. Macropinocytosis increases intracellular amino acid storage, promoting survival during amino acid deprivation. This metabolic shift depends on c-MYC downregulation, an early EMT event. Reintroducing c-MYC suppresses the metabolic switch, endolysosomal induction, macropinocytosis, and the proliferation-to-migration transition. These findings reveal how cells dynamically balance proliferation and invasion, offering insights into transition states difficult to capture in models of breast cancer metastasis.
    DOI:  https://doi.org/10.1101/2025.09.22.677807
  15. Sci Signal. 2025 Sep 30. 18(906): eadu7145
    Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer.
    Priya S Hibshman, Clint A Stalnecker, Jeffrey A Klomp, Kristina Drizyte-Miller, Jennifer E Klomp, A Cole Edwards, Lily M Pita, Richard G Hodge, J Nathaniel Diehl, Ryan D Mouery, Brandon L Mouery, Kayla R Snare, Andrew M Waters, Sen Peng, Natalie K Barker, Mariaelena Pierobon, Naim U Rashid, Nhan L Tran, Laura A Herring, Lee M Graves, Emanuel F Petricoin, Kirsten L Bryant, Adrienne D Cox, Channing J Der.
      Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.
    DOI:  https://doi.org/10.1126/scisignal.adu7145
  16. J Lipid Res. 2025 Oct 01. pii: S0022-2275(25)00182-8. [Epub ahead of print] 100920
    Cardiac lipid droplets differ under pathological and physiological conditions.
    Ni-Huiping Son, Sunny Son, Michael Verano, Zhen-Xiu Liu, Waqas Younis, Makenzie Komack, Kelly V Ruggles, Jana Gjini, Song-Tao Tang, Ainara Gonzalez Cabodevilla, Feng-Xia Liang, Hai-Zhen Wang, Dimitrios Nasias, José O Alemán, Ira J Goldberg.
      Excessive accumulation of lipids within cardiomyocytes can sometimes initiate cardiomyopathy, while in other situations excess lipids do not cause harm. To understand how pathologic and non-pathologic lipid accumulation differ, we isolated lipid droplets (LDs) from two genetically altered mouse lines and from wild-type (WT) mice after an overnight fast. The LDs from MHC-peroxisomal proliferator-activated receptor γ1(MHC-Pparg1) transgenic mice were 3-fold larger than those from either fasted WT or non-cardiomyopathy MHC-diacylglycerol acyl transferase 1 (MHC-Dgat1) transgenic mice. Proteomic analysis of the LD associated membrane proteins (LDAMPs) showed that MHC-Pparg1 LDs had less perilipin (Plin). Proteins associated with lipolysis and LD formation (CIDEs and MTP), lipid synthesis, and Pparg signaling pathways were increased in MHC-Pparg1 LDAMPs. Unlike in MHC-Pparg1, MHC-Dgat1 LDAMPs exhibited increased mitochondrial peroxidative proteins with reduced adipose triglyceride lipase (Pnpla2), and Pparg coactivator 1 alpha (Pgc1A). Cardiomyocytes from MHC-Pparg1 hearts had transmission electron microscopy (TEM) images of ongoing lipolysis and greater amounts of lipolytic proteins. In contrast, images from MHC-Dgat1 cardiomyocytes showed more lipophagy. Consistent with the proteomic study and EM images, cardiac immunofluorescence staining showed that Plin 5 protein, thought to block LD lipolysis, was markedly reduced with MHC-Pparg1 overexpression, while hormone sensitive lipase was increased. The autophagosome marker protein LC3B was increased in MHC-Dgat1 but not in MHC-Pparg1 hearts. Potentially toxic lipids like diacylglycerols and ceramides were increased in hearts but not LDs from MHC-Pparg1 mice. Our data indicates that cardiomyocyte LDs vary in size, composition, and metabolism. Cardiotoxicity was associated with greater LD lipolysis, which we postulate leads to intracellular release of toxic lipids.
    Keywords:  ceramides; heart failure; lipidomics; lipolysis; lipotoxicity; proteomics
    DOI:  https://doi.org/10.1016/j.jlr.2025.100920
  17. bioRxiv. 2025 Sep 26. pii: 2025.03.01.640992. [Epub ahead of print]
    Tissue Fluidity Mediates a Trade-off Between the Speed and Accuracy of Multicellular Patterning by Cell Sorting.
    Rikki M Garner, Sean E McGeary, Allon M Klein, Sean G Megason.
      The organization of cells into spatial patterns is a fundamental aspect of multicellularity. One major mechanism underlying tissue patterning is adhesion-based cell sorting, in which a heterogeneous mixture of cell types spontaneously separates into distinct domains based on differences in adhesion protein expression. Here, we identify tissue fluidity-the extent to which cells can move freely within a tissue-as a critical regulator of adhesion-based sorting. First, we describe a physically well-understood minimal tissue model that can integrate both tissue fluidity and adhesion-based sorting, and demonstrate that this model can quantitatively reproduce experimentally measured sorting dynamics in a fibroblast cell culture assay. We go on to show that altering tissue fluidity by any mechanism in the model leads to substantial changes in the rate or accuracy of sorting (or both). We further demonstrate that the balance between cell motility, which acts to fluidize the tissue, and homotypic cell-cell adhesion, which acts to solidify the tissue, sensitively tunes a fundamental trade-off between the rate and accuracy of sorting-such that sorting can only occur when motility and adhesion are tightly coupled. Intriguingly, best fits of the simulations to the experiments across a range of adhesion protein expression conditions suggest that cells may naturally scale their motility strength with their adhesion strength - thereby maintaining a permissive fluidity for sorting. Overall, our results indicate that tissue fluidity must be tightly regulated for sorting to occur, and that cells may have evolved a mechanism to naturally co-regulate their mechanical properties in order to sustain a patterning-competent fluidity.
    Statement of Significance: Tissue fluidity, or the ability of cells to freely rearrange within a tissue, is a universal property of multicellular organisms that plays central roles in development, cancer, and wound healing. Here, we identify tissue fluidity as a critical regulator of a major mechanism of multicellular patterning - adhesion-based cell sorting. The results of our combined experimental-computational investigation suggest that tissues can readily tune their fluidity in order to freeze, catalyze, or erase multicellular patterns - carrying significant implications for our understanding of how patterns are formed in development, lost in diseases affecting tissue organization (e.g., cancer), regained through the processes of wound healing and regeneration, and can be engineered in the creation of synthetic organoid and embryoid systems.
    One sentence summary: Biophysical modeling demonstrates how tissue fluidity is a key regulator of the rate and accuracy of adhesion-based sorting.
    DOI:  https://doi.org/10.1101/2025.03.01.640992
  18. bioRxiv. 2025 Sep 26. pii: 2025.09.25.678303. [Epub ahead of print]
    Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    One-Sentence Summary: Aging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.
    DOI:  https://doi.org/10.1101/2025.09.25.678303
  19. bioRxiv. 2024 Jul 26. pii: 2024.07.26.605291. [Epub ahead of print]
    Development of a new flippase-dependent mouse model for red fluorescence-based isolation of Kras G12D oncogene-expressing tumor cells.
    Dusan Hrckulak, Michaela Krausova, Jakub Onhajzer, Monika Stastna, Vitezslav Kriz, Lucie Janeckova, Vladimir Korinek.
      Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant Kras, selective isolation and analysis of transforming or tumor cells that produce the Kras oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant Kras G12D that enables the "activation" of Kras G12D expression together with production of red fluorescent protein tdTomato. Both proteins are expressed from the endogenous Kras locus after recombination of a transcriptional stop box in the genomic DNA by the enzyme flippase (Flp). We have demonstrated the functionality of the allele termed RedRas (abbreviated Kras RR ) under in vitro conditions with mouse embryonic fibroblasts and organoids and in vivo in the lung and colon epithelium. After recombination with adenoviral vectors carrying the Flp gene, the Kras RR allele itself triggers formation of lung adenomas. In the colon epithelium, it causes the progression of adenomas that are triggered by the loss of tumor suppressor adenomatous polyposis coli (Apc). Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that Kras G12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the Kras G12D function is effectively suppressed by specific inhibitor MRTX1133.
    DOI:  https://doi.org/10.1101/2024.07.26.605291
  20. Mol Cell. 2025 Oct 02. pii: S1097-2765(25)00714-2. [Epub ahead of print]85(19): 3554-3561
    A needed nomenclature for nucleosomes.
    Michael-Christopher Keogh, Genevieve Almouzni, Andrew J Andrews, Karim-Jean Armache, Cheryl H Arrowsmith, Sung Hee Baek, Mark T Bedford, Emily Bernstein, Jacques Côté, Yael David, John M Denu, Beat Fierz, Benjamin A Garcia, Karen C Glass, Or Gozani, Kristian Helin, Steven Henikoff, Ole N Jensen, Steven Z Josefowicz, Neil L Kelleher, Tatiana G Kutateladze, Herbert H Lindner, Chao Lu, Karolin Luger, Parag Mallick, Catherine A Musselman, Tom W Muir, Ljiljana Paša-Tolić, Robert Schneider, Xiaobing Shi, Yang Shi, Simone Sidoli, Lloyd M Smith, Jessica K Tyler, Cynthia Wolberger, Jerry L Workman, Brian D Strahl, Nicolas L Young.
      Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform to describe the particular gathering of histones within an individual nucleosome. There is now a need to define specific forms of these entities in prose while providing space for experimental nuance. To this end, we introduce a nomenclature that can express discrete PTMs, proteoforms, nucleoforms, or situations where defined PTMs exist in an uncertain context. Though specifically designed for the chromatin field, adaptions of the framework could be used to describe-and thus dissect-how proteoforms are configured in functionally distinct complexes across biology.
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.029
  21. Nucleic Acids Res. 2025 Sep 30. pii: gkaf968. [Epub ahead of print]
    CRESTA: a comprehensive transcriptome atlas for cellular response to external stressors.
    Hongge Wang, Weiping Mu, Xiaoqiong Bao, Luowanyue Zhang, Yuxi Xie, Huiqin Li, Kebing Wang, Yaqing Cao, Jingsong Chen, Jikai Zhan, Lingxiao Li, Jun Shen, Jian Ren, Zhixiang Zuo.
      Cellular stress response (CSR) is crucial for maintaining intracellular homeostasis upon exposure to hazardous environmental stressors, whose failure can lead to cell death. Here, we developed CRESTA (https://cresta.renlab.cn/), an integrated database providing a comprehensive resource for studying stressor-induced CSR. CRESTA unifies fragmented transcriptomic data across diverse stressors, cell types, and contexts into a hierarchically structured atlas. It catalogs 20 786 unique stress-associated genes responding to 14 major categories (180 sub-categories) of human cellular stressors, based on the differential expression analysis of 8258 samples spanning 197 human cell types. These stressor categories include air pollutants, antineoplastic agents, heavy metals, hypoxia, mechanical stimuli, natural toxins, nutrient deprivation, pesticides, radiation, temperature change, etc. To further enable causal inference between stressors and molecular pathologies, CRESTA links CSR transcriptomic signatures to functional pathways, cell death annotations, and disease associations. Additionally, the CSR profiles are connected with chemical perturbation features involving FDA-approved drugs to support systematic drug repurposing. Overall, we expect that CRESTA will serve as a vital resource for mechanistic studies of cytotoxicity, cellular perturbation evaluation, and CSR-targeted drug discovery.
    DOI:  https://doi.org/10.1093/nar/gkaf968
  22. Eur J Cancer Prev. 2025 Sep 29.
    Association between weight loss and overall survival in patients with pancreatic cancer: a meta-analysis.
    Guofang Wang, Xuan Tang, Shijun Wang, Yu Fan.
      Weight loss is a common symptom among patients with pancreatic cancer, often indicating tumor progression or poor nutritional status. This meta-analysis aimed to investigate the association between weight loss and overall survival in individuals with pancreatic cancer, synthesizing evidence from observational studies. A thorough search of the PubMed, Embase, and Web of Science databases was conducted up to 18 May 2025. Eligible studies must have reported quantitative associations between percent weight loss and overall survival in patients with pancreatic cancer. The adjusted hazard ratios with 95% confidence intervals (CIs) were pooled using a random-effects model to account for clinical heterogeneity. Eleven observational studies, comprising 1649 patients with pancreatic cancer were included. The pooled result showed that weight loss was significantly associated with reduced overall survival (hazard ratio: 1.55, 95% CI: 1.29-1.85). Subgroup analyses revealed stronger associations in patients aged 65 years or over (hazard ratio: 1.64, 95% CI: 1.28-2.10) and those assessed for weight loss during treatment (hazard ratio: 2.20, 95% CI: 1.68-2.89), compared with their counterparts; however, there was no clear association between weight loss and overall survival (hazard ratio: 1.27, 95% CI: 0.99-1.61) in pancreatic ductal adenocarcinoma subgroup. Weight loss serves as an independent prognostic factor for reduced overall survival in pancreatic cancer. Clinicians should prioritize nutritional assessment in patients with weight loss to inform personalized care strategies; however, further prospective studies are needed to validate these findings and elucidate underlying mechanisms.
    Keywords:  meta-analysis; overall survival; pancreatic cancer; weight loss
    DOI:  https://doi.org/10.1097/CEJ.0000000000000990
  23. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2514995122
    Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling.
    Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L Elson, Xi-Qiao Feng, Guy M Genin.
      Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell-cell communication ([Formula: see text]100 to 200 [Formula: see text]m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model reveals that the critical stretch ratio at which fibrous networks transition from compliant to strain-stiffening governs this threshold through the formation of tension bands between neighboring cells. These mechanical communication networks drive collective phase transition in tissue condensation when cell density exceeds an effective percolation threshold. Our model explains how microscale cell-ECM interactions control emergent mechanical properties in biological systems and offers insight both into the physics of inhomogeneous materials under active stress, and into potential mechanical interventions for wound healing and fibrotic disorders.
    Keywords:  cell–cell communication through fibrous ECM; mechanobiology; phase transitions; phenotypic transformation; tissue remodeling
    DOI:  https://doi.org/10.1073/pnas.2514995122
  24. Nat Commun. 2025 Sep 30. 16(1): 8732
    Aging: the wound that never starts healing.
    Mikolaj Ogrodnik.
      Aging is a complex biological process leading to functional decline and disease susceptibility. This article proposes that chronic activation of tissue damage response mechanisms drives aging, with aged organs exhibiting features similar to those seen after acute injury, such as histolysis, inflammation, immune cell infiltration, accumulation of lipid droplets, and induction of cellular senescence. The overlap between injury and aging phenotypes is supported by evidence that interventions slowing aging often impair healing, and vice versa. This perspective offers a unifying framework to understand aging and suggests new directions for treating age-related diseases, cancer, and the aging process.
    DOI:  https://doi.org/10.1038/s41467-025-64462-3
  25. Cancer Res. 2025 Oct 01. OF1-OF3
    Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
    Désirée Schatton, Christian Frezza.
      Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3356
  26. Autophagy. 2025 Oct 02.
    Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.
    Jinghong Yang, Haobin Sun, Keqing Xu, Xiaomei Zhang, Mudan Huang, Guanghui Jin, Yasong Liu, Weizhao Chen, Shunan Lin, Juan Shen, Chuan-Qi Zhong, Yan Xu, Qi Zhang, Wei Liu, Yang Yang, Jingxing Ou.
      Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.
    Keywords:  Aging; DNA damage; DRAM1; autophagy; metabolism; senescence
    DOI:  https://doi.org/10.1080/15548627.2025.2568487
  27. ACS Macro Lett. 2025 Sep 29. 1484-1491
    Theory of Condensate Size Control by Molecular Charge Asymmetry.
    Chengjie Luo, Nathaniel Hess, Dilimulati Aierken, Yicheng Qiang, Jerelle A Joseph, David Zwicker.
      Biomolecular condensates are complex droplets comprising diverse molecules that interact by various mechanisms. Condensation is often driven by short-range attraction, but net charges can also mediate long-range repulsion. Using molecular dynamics simulations and an equilibrium field theory, we show that such opposing interactions can suppress coarsening, so many droplets of equal size coexist at equilibrium. This size control depends strongly on the charge asymmetry between molecular constituents, while the strength of the short-range attractions has a weak influence. The mechanism relies on droplets expelling ions; therefore, they cannot screen electrostatics effectively, implying that droplets acquire a net charge and cannot grow indefinitely. Our simulations indicate that this effect is likely less prevalent in biomolecular condensates within cells, although we still observe stable small clusters in this case. Taken together, our work reveals that electrostatic effects through molecular charge asymmetries can control droplet size, which contributes to our understanding of biomolecular condensates and the creation of synthetic patterns in chemical engineering.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00342
  28. Biochem Biophys Res Commun. 2025 Sep 25. pii: S0006-291X(25)01431-7. [Epub ahead of print]785 152715
    ApoCIII-induced hyperlipidemia alters lipid packing in erythrocyte membranes without affecting fluidity.
    Yandara Akamine Martins, Cristiany Shultz, Nilton Rodrigues, Maria Ida Bonini Ravanelli, Jesui Vergilio Visentainer, Oscar de Oliveira Santos, Jairo Berti, Kellen Brunaldi.
      High levels of apolipoprotein CIII (apoCIII) promotes hypertriglyceridemia and increased risk of cardiovascular disease. However, the impact of apoCIII-induced hyperlipidemia on membrane composition and fluidity of red blood cells (RBC) is still unclear. Here, we report the fluidity, ordering, and lipid composition of the plasma membrane of RBC from transgenic mice that overexpress the human apoCIII. ApoCIII mice displayed marked hypertriglyceridemia (∼8-fold increase), moderate hypercholesterolemia (1.6-fold increase), followed by a shift toward increased plasma fatty acid unsaturation. RBC membranes from apoCIII mice demonstrated a significant increase in cholesterol content and cholesterol-to-phospholipid ratio, without alterations in sphingomyelin levels and the four major fatty acid analyzed. Fluorescence measurements using the probe Laurdan revealed unchanged membrane fluidity (anisotropy), but a significant reduction in generalized polarization (GP), indicative of increased lipid disorder and hydration at the phospholipid headgroup region. These findings suggest that moderate plasma cholesterol elevation alters RBC membrane lipid packing without affecting global fluidity or fatty acid profile. Overall, this study provides novel biophysical insights into the effects of dyslipidemia on erythrocyte membranes and support the potential of RBC membrane properties as sensitive biomarkers of systemic lipid perturbations.
    Keywords:  Cholesterol; Lipid order; Lipoprotein; Phospholipid; Triglyceride
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152715
  29. Nature. 2025 Oct 01.
    A pathway that controls conversion of the amino acid cysteine into a cholesterol regulator.
      
    Keywords:  Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-03159-5
  30. Am J Physiol Cell Physiol. 2025 Oct 03.
    Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.
    Alastair A E Saunders, Chris Karagiannis, Wayne X Du, Lauren S James, Rachel E Thomson, Robin L Anderson, Paul Gregorevic.
      Cancer-associated cachexia decreases quality of life, reduces therapy response, and diminishes survival prospects. Effective cachexia countermeasures remain a significant unmet need. Research into cancer cachexia has made extensive use of models of colon, lung and pancreatic cancers. However, while cachexia also affects people with metastatic breast cancer, the mechanisms underlying breast cancer-associated cachexia are relatively understudied. Thus, we sought to investigate orthotopic mouse models of metastatic breast cancer for the progression of cachexia, with a focus on muscle wasting given its role in the frailty that is a hallmark of the condition. Female Balb/c mice received an intramammary fat pad injection of 4T1.2 or EMT6.5 cells, and NSG mice received MDA-MB-231-HM (231-HM) cells, to induce primary breast tumors that were subsequently excised. The resultant metastatic burden after approximately 4 weeks led to variable loss of muscle mass (tibialis anterior: EMT6.5: -17.1%, 231-HM: -13.5%, 4T1.2: -9.5%) and fat mass (gonadal fat: EMT6.5: -75.1%, 231-HM: -62.5%, 4T1.2: -30.2%). Muscle protein synthesis markers were decreased in EMT6.5 tumor-bearing mice. Distinct increases in the abundance of mRNA for E3-ubiquitin ligase and autophagy-related genes were observed between models. Neuromuscular junction perturbations were observed in EMT6.5 and 4T1.2 tumor-bearing mice. Neutrophilia was noted in the muscles of EMT6.5 tumor-bearing mice. The findings show that muscle mass and function are reduced in mouse models of metastatic breast cancer. Further study of these models could provide useful insights with which to better understand the diversity of cachexia progression across different cancer types.
    Keywords:  Breast cancer; cachexia; metastasis; neuromuscular junction; neutrophil
    DOI:  https://doi.org/10.1152/ajpcell.00230.2025
  31. Nat Commun. 2025 Sep 30. 16(1): 8714
    Best practices and tools in R and Python for statistical processing and visualization of lipidomics and metabolomics data.
    Jakub Idkowiak, Jonas Dehairs, Jana Schwarzerová, Dominika Olešová, Jacob X M Truong, Aleš Kvasnička, Marios Eftychiou, Ruben Cools, Xander Spotbeen, Robert Jirásko, Vullnet Veseli, Marco Giampà, Vincent de Laat, Lisa M Butler, Wolfram Weckwerth, David Friedecký, Jonas Demeulemeester, Karel Hron, Johannes V Swinnen, Michal Holčapek.
      Mass spectrometry-based lipidomics and metabolomics generate extensive data sets that, along with metadata such as clinical parameters, require specific data exploration skills to identify and visualize statistically significant trends and biologically relevant differences. Besides tailored methods developed by individual labs, a solid core of freely accessible tools exists for exploratory data analysis and visualization, which we have compiled here, including preparation of descriptive statistics, annotated box plots, hypothesis testing, volcano plots, lipid maps and fatty acyl chain plots, unsupervised and supervised dimensionality reduction, dendrograms, and heat maps. This review is intended for those who would like to develop their skills in data analysis and visualization using freely available R or Python solutions. Beginners are guided through a selection of R and Python libraries for producing publication-ready graphics without being overwhelmed by the code complexity. This manuscript, along with associated GitBook code repository containing step-by-step instructions, offers readers a comprehensive guide, encouraging the application of R and Python for robust and reproducible chemometric analysis of omics data.
    DOI:  https://doi.org/10.1038/s41467-025-63751-1
  32. Nature. 2025 Oct 01.
    Proteotoxic stress response drives T cell exhaustion and immune evasion.
    Yi Wang, Anjun Ma, No-Joon Song, Ariana E Shannon, Yaa S Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A Saadey, Amir Yousif, Gautam Ghosh, Jay K Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching-Cheng Huang, Ruoning Wang, Christian M Beusch, Abdelhameed S Dawood, David E Gordon, Mohamed S Abdel-Hakeem, Hazem E Ghoneim, Gang Xin, Brian C Searle, Zihai Li.
      Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09539-1
  33. Brief Bioinform. 2025 Aug 31. pii: bbaf521. [Epub ahead of print]26(5):
    SurvBoard: standardized benchmarking for multi-omics cancer survival models.
    David Wissel, Nikita Janakarajan, Aayush Grover, Enrico Toniato, Maria Rodríguez Martínez, Valentina Boeva.
      Multi-omics data, which include genomic, transcriptomic, epigenetic, and proteomic data, are gaining increasing importance for determining the clinical outcomes of cancer patients. Several recent studies have evaluated various multimodal integration strategies for cancer survival prediction, highlighting the need for standardizing model performance results. Addressing this issue, we introduce SurvBoard, a benchmark framework that standardizes key experimental design choices. SurvBoard enables comparisons between single-cancer and pan-cancer data models and assesses the benefits of using patient data with missing modalities. We also address common pitfalls in preprocessing and validating multi-omics cancer survival models. We apply SurvBoard to several exemplary use cases, further confirming that statistical models tend to outperform deep learning methods, especially for metrics measuring survival function calibration. Moreover, most models exhibit better performance when trained in a pan-cancer context and can benefit from leveraging samples for which data of some omics modalities are missing. We provide a web service for model evaluation and to make our benchmark results easily accessible and viewable: https://www.survboard.science/. All code is available on GitHub: https://github.com/BoevaLab/survboard/. All benchmark outputs are available on Zenodo: 10.5281/zenodo.11066226. A video tutorial on how to use the Survboard leaderboard is available on YouTube at https://youtu.be/HJrdpJP8Vvk.
    Keywords:  cancer; deep learning; multi-omics; survival analysis
    DOI:  https://doi.org/10.1093/bib/bbaf521
  34. bioRxiv. 2024 May 03. pii: 2024.05.01.592039. [Epub ahead of print]
    Co-occurring Mutations in Different Genes Can Fuel Oncogenic Signaling and Serve as Metastatic Tumor Markers.
    Bengi Ruken Yavuz, Ugur Sahin, Hyunbum Jang, Ruth Nussinov, Nurcan Tuncbag.
      Interrogation of big genomic data and integration with large-scale protein-protein interaction networks and pathways, can provide deep patterns that are rare- yet can prompt dramatic phenotypic alterations and serve as clinical signatures. Mapping cancer-specific co-occurring mutation-pair signatures, in primary and metastatic tumors, is indispensable in precision oncology. The additivity of co-occurring driver mutations in different genes ( in trans ) can lead to powerful proliferation signals. Co-occurring rare in trans combinations can serve as metastasis markers; excluded combinations may indicate candidates for oncogene-induced senescence (OIS), a tumor-suppressive mechanism. Our statistical framework of the pan-cancer mutation profiles of ∼60,000 tumor sequences from the TCGA and AACR GENIE databases, identified 3424 statistically significant different double mutations in non-redundant pathways, that is, have different downstream targets that may promote specific cancers through single or multiple pathways. Our analysis indicates that they are mostly in primary tumors. We list actionable in trans mutations for 2385 metastatic tumors and provide co-occurrence trees of metastatic breast- cancer markers. This innovative work clarifies the mechanistic conceptual basis and establishes the first of its kind tool for identifying and predicting metastasis. Crucially, when coupled with their proliferative functions and pathways, and linked with drugs, it could provide an invaluable metastasis-targeting resource.
    DOI:  https://doi.org/10.1101/2024.05.01.592039
  35. J Biochem. 2025 Sep 30. pii: mvaf056. [Epub ahead of print]
    FRET-based biosensor moxCRONOS enables quantitative monitoring of macromolecular crowding in organelles and protein aggregates.
    Yurina Nakajima, Hiroaki Suzuki, Tamami Miyagi, Kohsuke Kanekura.
      Macromolecular crowding is a fundamental property of the intracellular environment that influences protein folding, enzymatic activity, and phase behavior. Disruptions to the homeostasis of macromolecular crowding can drive pathological processes, such as aberrant liquid-liquid phase separation and protein aggregation, which are central features of several neurodegenerative diseases. However, tools for quantifying crowding and aggregation remain limited. Here, we describe moxCRONOS, a Förster resonance energy transfer (FRET)-based biosensor that enables the quantitative measurement of macromolecular crowding and protein condensation. moxCRONOS retains the optical properties of the original CRONOS sensor but offers enhanced stability in oxidative environments, such as within the endoplasmic reticulum or under sodium arsenite treatment, allowing for direct comparison of crowding levels across organelles regardless of redox conditions. Moreover, when fused to dipeptide repeat proteins associated with C9ORF72-linked neurodegeneration, moxCRONOS detects aggregation-prone states-especially in cells expressing glycine-alanine (GA) repeats. Using fluorescence-activated cell sorting, we achieved sensitive and quantitative detection of heterogeneous high-FRET cell populations containing GA aggregates. FRET signal intensity increased upon treatment with a molecular crowding agent or a proteasome inhibitor. These findings establish moxCRONOS as a versatile biosensor for investigating both physiological macromolecular crowding and pathological protein aggregation, with significant potential for disease modeling and therapeutic screening.
    Keywords:  Biosensor; FRET; LLPS; Macromolecular crowding; Protein aggregation
    DOI:  https://doi.org/10.1093/jb/mvaf056
  36. PLoS Comput Biol. 2025 Sep 30. 21(9): e1013477
    A computational framework for the investigation of phosphoinositide regulation.
    Hilaire Yam Fung Cheung, Chukiat Tantiwong, Dipali Kale, Jonathan M Gibbins, Steve P Watson, Johan W M Heemskerk, Albert Sickmann, Robert Ahrends, Joanne L Dunster.
      Phosphoinositides are a group of interconvertible lipids that are located in the membrane of eukaryotic cells. They turnover via complex network of reactions (called the phosphoinositide pathway) that respond rapidly to regulate many aspects of a cell's response to their environment. Given their low-abundance they are difficult to characterise experimentally. Here we utilise a new experimental method to generate an unusually large dataset that characterises the time-dependent changes in five membrane bound phospoinositides and a soluble inositide in platelet, downstream of its GPVI receptor, where we know the phosphoinositide pathway is particularly active. To shed light on regulatotory steps that are often opaque to experimentation we use this data within a mathematical and computational framework. We construct and assess eleven mathematical models that represent competing interpretations of the dominant mechanisms that regulate the pathway. We find that while four of the models can generate the available data only one model, that incorporates an additional pool of PtdIns, is consistent with the data and is able to successfully predict the effects of an inhibitor. We publish all models openly in a form that is easily usable and adaptable for other researchers to use alongside our or their own data. We studied how changes in the shape and magnitude of events that stimulate the phosphoinositide pathway affect its dynamics. Despite these perturbations, the abundance of Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) remained stable, consistent with findings reported in the literature.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013477
  37. Nat Med. 2025 Sep 29.
    Prevention of type 2 diabetes through prediabetes remission without weight loss.
    Arvid Sandforth, Elsa Vazquez Arreola, Robert L Hanson, Nicolai J Wewer Albrechtsen, Jens Juul Holst, Robert Ahrends, Cristina Coman, Felicia Gerst, Estela Lorza-Gil, Yurong Cheng, Leontine Sandforth, Sarah Katzenstein, Marlene Ganslmeier, Jochen Seissler, Hans Hauner, Nikolaos Perakakis, Robert Wagner, Jürgen Machann, Fritz Schick, Andreas Peter, Rainer Lehmann, Cora Weigert, Jennifer Maurer, Hubert Preissl, Martin Heni, Julia Szendrödi, Stefan Kopf, Michele Solimena, Peter Schwarz, Matthias Blüher, Hans-Ulrich Häring, Martin Hrabé de Angelis, Annette Schürmann, Stefan Kabisch, Knut Mai, Andreas F H Pfeiffer, Stefan Bornstein, Michael Stumvoll, Michael Roden, Norbert Stefan, Andreas Fritsche, Andreas L Birkenfeld, Reiner Jumpertz von Schwartzenberg.
      Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.
    DOI:  https://doi.org/10.1038/s41591-025-03944-9
  38. Methods Mol Biol. 2026 ;2963 79-89
    Lipidomic Sample Preparation to Detect Phosphatidylcholine Alterations in Skeletal Muscle.
    William J Valentine, Suzumi M Tokuoka, Yoshihiro Kita, Hideo Shindou.
      Altered phospholipid compositions in skeletal muscle occur in muscular dystrophy and other pathological conditions; however, origins and relationships to the disease course are unclear. Liquid chromatography-mass spectrometry (LC-MS) technologies allow the determination of phospholipid compositions and alteration patterns in disease states. Here, we describe a basic protocol to prepare methanolic extracts from skeletal muscle, which may be analyzed by lipidomic LC-MS in order to detect compositional alterations in phosphatidylcholine, a major phospholipid species of skeletal muscle, as well as other phospholipid classes such as phosphatidylethanolamine. These analyses are useful to determine relative increases or decreases in individual phospholipid species between samples and capture changes in membrane compositions rather than the absolute quantities of lipids. LC-MS lipidomic analyses often yield large datasets containing hundreds of chromatographic peaks for each sample, and a ratiometric analysis strategy to determine the relative abundances of the major PC species is also briefly introduced.
    Keywords:  Lipidomic analyses; Muscular dystrophy; Phosphatidylcholine; Phospholipid compositions; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-4738-7_5
  39. Nat Cell Biol. 2025 Oct 03.
    CellNavi predicts genes directing cellular transitions by learning a gene graph-enhanced cell state manifold.
    Tianze Wang, Yan Pan, Fusong Ju, Shuxin Zheng, Chang Liu, Yaosen Min, Qun Jiang, Xinwei Liu, Huanhuan Xia, Guoqing Liu, Haiguang Liu, Pan Deng.
      A select few genes act as pivotal drivers in the process of cell state transitions. However, finding key genes involved in different transitions is challenging. Here, to address this problem, we present CellNavi, a deep learning-based framework designed to predict genes that drive cell state transitions. CellNavi builds a driver gene predictor upon a cell state manifold, which captures the intrinsic features of cells by learning from large-scale, high-dimensional transcriptomics data and integrating gene graphs with directional connections. Our analysis shows that CellNavi can accurately predict driver genes for transitions induced by genetic, chemical and cytokine perturbations across diverse cell types, conditions and studies. By leveraging a biologically meaningful cell state manifold, it is proficient in tasks involving critical transitions such as cellular differentiation, disease progression and drug response. CellNavi represents a substantial advancement in driver gene prediction and cell state manipulation, opening new avenues in disease biology and therapeutic discovery.
    DOI:  https://doi.org/10.1038/s41556-025-01755-1
  40. bioRxiv. 2025 Feb 17. pii: 2025.02.15.638347. [Epub ahead of print]
    Pericyte-tumor crosstalk facilitates metastatic tumor cell latency through PIEZO1-activated lysophospholipid transfer.
    Tamara McErlain, Morgan J Glass, Elizabeth C McCulla, Caitlin A Madden, Lauren E Ziemer, Kirsten E Overdahl, Alan K Jarmusch, Michael J Kruhlak, Alexander T Chesler, Howard H Yang, Maxwell P Lee, Cristina M Branco, Meera Murgai.
      Tumor dissemination is increasingly recognized to begin early in tumor development. Although most of these early disseminated cells are cleared, some survive and persist below clinical detection, acting as reservoirs for metastatic relapse. Metastatic tumor cells often rely on interactions with local stromal cells to support their colonization. In this study, we propose that pericyte-tumor cell interactions promote dormancy induction in the early metastatic lung, enhancing disseminated tumor cell (DTC) persistence. Extravital imaging demonstrated that DTCs interact with pericytes upon extravasation into the lung. Co-culture experiments were used to assess DTC fate after pericyte contact and revealed that transient contact with pericytes reduced the proliferation of metastatic 4T1 breast cancer cells but had no effect on non-metastatic 67NR cells. In vivo , transient pericyte contact resulted in higher lung metastatic burden, driven by small, non-proliferative lesions (<6 cells), 10 days after intracardiac injection. These lesions exhibited reduced KI67 staining and EdU incorporation compared to those from monocultured cells. We further observed that primary lung pericytes transferred lyso-phospholipids (lyso-PLs) specifically to metastatic 4T1 cells through direct contact. Gene expression analysis indicated that transient pericyte contact activated pathways related to syncytium formation in metastatic cells. In normal physiology, pericytes act in a syncytium to regulate blood flow via mechanosensitive channels in response to blood pressure changes. We hypothesize that tumor cells exploit these mechanosensitive responses to trigger lyso-PL transfer from pericytes. Supporting this, calcium imaging showed higher calcium activity in pericytes co-cultured with 4T1 cells, and calcium channel inhibitors significantly reduced lyso-PL transfer. Pharmacological activation of pericyte calcium channels induced lyso-PL release, which was subsequently taken up by tumor cells. Conditioned medium from activated pericytes, containing free lyso-PLs, recapitulated the reduced proliferation observed in transient co-culture. Finally, we found our pericyte-induced dormancy signature to be associated with tumor dormancy and distant metastasis free survival latency in breast cancer patients. Together, these findings suggest that early DTCs may exploit pericyte signaling mechanisms to enter dormancy, facilitating their persistence at metastatic sites and contributing to future relapse.
    DOI:  https://doi.org/10.1101/2025.02.15.638347
  41. Smart Mol. 2025 Sep;3(3): e70015
    A ratiometric fluorescent probe monitoring lipid peroxidation within lipid droplets in foam cells.
    Dingxuan Li, Caiwei Lu, Shulan Sun, Xiaoxi Li, Yi Xiao, Xinfu Zhang.
      Lipid peroxidation (LPO) in foam cells is crucial for regulating atherosclerosis progression. It correlates with lipid uptake and the state of lipid droplets. In this study, we report a lipid droplet-targeted fluorescent LPO probe, Ld-LPO. It selectively responds to LPO, resulting in a significant fluorescence shift from 590 to 525 nm, enabling a ratiometric imaging of LPO in lipid droplets. Ld-LPO traces lipid droplets in foam cells, revealing a correlation between LPO and lysosomal engulfment. We found that lipid droplets engulfed by lysosomes exhibit higher LPO, attributed to low-density lipoprotein accumulation in lysosomes. Furthermore, Ld-LPO is compatible with dual-color flow cytometry, facilitating high-throughput analysis of LPO in foam cells.
    Keywords:  foam cells; lipid droplets; lipid peroxidation; ratiometric probe
    DOI:  https://doi.org/10.1002/smo2.70015
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