bims-cagime 2026-09-20 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–09–20
39 papers selected by
Kıvanç Görgülü, Technical University of Munich

Pancreatic ductal adenocarcinoma: The Vision of Heracles.
Daraxonrasib (Rasonque) for metastatic pancreatic cancer.
Cysteine excess triggers a mitochondrial iron-dependent cell death.
PRMT1-Mediated Arginine Methylation Redirects SMAD4 Signaling to Promote Metastasis in Pancreatic Cancer.
Calcium licenses lipid droplets for ferroptosis: A PKCβ-ACSL4-ALOX15 phosphorylation relay.
Topological defects mediate collective transport of confluent cells.
Chemotherapy-free phase 1/2 trial of HRS-4642 plus adebrelimab in previously treated metastatic KRAS G12D-mutant pancreatic cancer.
Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.
NINJ1: implications for plasma membrane rupture and disease.
Metabolic matching shapes organ-specific metastasis.
Evolving Cell with evolving science.
Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
A Stiff Achilles' Heel: How Tumor Mechanics Shape Metastatic Vulnerability.
FDA Approves New Treatment for Advanced Pancreatic Cancer.
Real-time quality control in optoacoustic mesoscopy for enhancing data quality and standardization in clinical studies.
Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.
DFCP1-containing ER microdomains mediate lysosomal membrane repair.
Lack of tumor-derived LCN2 sensitizes pancreatic cancer cells to ferroptosis induction.
Decreased FSP1 expression under chronic hypoxia sensitizes human macrophages towards ferroptosis.
Viscotaxis: An Emerging Driver for Directed Cell Migration.
GICPIdb: an archival repository of multimodal data focusing on pathological images for gastrointestinal cancers.
Lkb1 loss links dietary lipids to cancer cachexia.
R0 Resection improves survival after multivisceral resection for pancreatic ductal adenocarcinoma.
Type I interferons modulate autophagy to shape gemcitabine response in pancreatic cancer cells.
MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.
Targeting valine metabolism and ferroptosis to overcome chemoresistance in PDAC.
T cells are blind to the dark mechanics of tumors.
Nitrated fatty acids form membrane biochemical capacitors that restrain inflammation.
ARNTL2 promotes metastatic phenotypes through SERPINE1 transcription in KRAS G12D pancreatic cancer.
Exercise as a multisystem signaling therapy: A hypothesis integrating inter-organ communication and membrane microdomain regulation in metabolic disease.
Activating a patient-relevant pathogenic variant of a genetically defined heart disease in a humanized pig model.
CFM: confinement force microscopy-a dynamic, precise and stable microconfiner for traction force microscopy in spatial confinement.
DisPhaseDB 2.0: Improved interpretation of disease-associated variants in liquid-liquid phase separation proteins with agent-accessible querying.
Analyzing model inaccuracy and relative importance of parameters of discrete model of adhesion of circulating tumor cells for investigating metastatic dynamics.
Programmed ribosomal frameshifting triggers translational stress to promote viral replication.
Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
Balanced contractility and adhesion drive polarization in a minimal elastic actomyosin network.
Biophysical and molecular determinants of NCOA4-mediated ferritinophagy at the ferroptosis-inflammation interface: Compartmental iron transport, lipid oxidation, and causal constraints.
Broadband backscattering confocal microscopy enables label-free 3D live cell nanoscale sensitive imaging.

Cancer Cell. 2026 Sep 14. pii: S1535-6108(26)00352-1. [Epub ahead of print]44(9): 1721-1726

Pancreatic ductal adenocarcinoma: The Vision of Heracles.

European Pancreatic Club (EPC) Pancreatic Cancer Think Tank Group

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, as tumors evolve faster than therapies. Resistance is ecological, not merely KRAS driven, involving overlooked players like high-grade pancreatic intraepithelial neoplasias (PanINs), peripancreatic fat, stromal mechanics, myeloid-neural circuits, metabolic rewiring, and systemic host responses. We propose precision interception targeting PanIN/intraductal papillary mucinous neoplasm (IPMN) biology, spatial-functional-proteogenomic classification beyond transcriptomics, the Heracles Protocol (measure, prime, strike, and adapt), and integrated technologies from AI pathology to exosomal delivery and CRISPR-based synergy mapping, together making PDAC more tractable.

DOI: https://doi.org/10.1016/j.ccell.2026.07.014
Med Lett Drugs Ther. 2026 Sep 28. 68(1764): 154-155

Daraxonrasib (Rasonque) for metastatic pancreatic cancer.



Keywords:  Rasonque; adverse effects; daraxonrasib; dosage; drug interactions; efficacy; pancreatic cancer; safety

DOI:  https://doi.org/10.58347/tml.2026.1764b
Nat Metab. 2026 Sep 15.

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

DOI: https://doi.org/10.1038/s42255-026-01616-7
Cancer Res. 2026 Sep 15.

PRMT1-Mediated Arginine Methylation Redirects SMAD4 Signaling to Promote Metastasis in Pancreatic Cancer.

Yizhou Liu, Xueyi Liang, Ruozheng Wei, Yu Peng, Gengdu Qin, Jiaying Liu, Yuhan Zhao, Hongkun Cai, Taoyu Chen, Shanmiao Gou, Tao Yin, Bo Wang, Heshui Wu, Yingke Zhou.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastatic dissemination and poor clinical outcomes. Although SMAD4 is frequently altered in PDAC, the majority of tumors retain wild-type SMAD4, which paradoxically acquires pro-metastatic functions during disease progression. Uncovering how SMAD4 transcriptional output is reprogrammed to support metastasis in advanced PDAC could reveal strategies to prevent and treat metastasis. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a critical modifier that mediates a metastasis-promoting transcriptional state of SMAD4. PRMT1 catalyzed asymmetric dimethylation of SMAD4 at arginine 272 (R272), a modification that did not alter SMAD4 expression but stabilized nuclear SMAD2/3-SMAD4 complexes and redirected SMAD4 chromatin engagement toward epithelial-mesenchymal transition (EMT) gene programs. Mechanistically, R272-methylated SMAD4 promoted the recruitment of a BRG1-CTCF transcriptional complex, enabling chromatin-dependent activation of pro-metastatic transcriptional outputs. Importantly, pharmacological inhibition of PRMT1, particularly in combination with BRG1 degradation, dismantled methylation-dependent SMAD4 transcriptional complexes, suppressed EMT programs, and markedly reduced liver metastasis in preclinical PDAC models. Together, these findings uncover a post-translational mechanism that governs SMAD4 transcriptional specificity and identify PRMT1-dependent methylation as a therapeutic vulnerability in SMAD4-wild-type pancreatic cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0923
Cell Calcium. 2026 Sep 11. pii: S0143-4160(26)00087-4. [Epub ahead of print]138 103194

Calcium licenses lipid droplets for ferroptosis: A PKCβ-ACSL4-ALOX15 phosphorylation relay.

Adnan Amin, Wajid Zaman.

  Ferroptosis is executed by iron-dependent phospholipid peroxidation, yet the upstream signals that determine when oxidizable lipid pools become lethal remain incompletely resolved. Recent work identifies a calcium-dependent protein kinase C beta (PKCβ) pathway that phosphorylates acyl-CoA synthetase long-chain family member 4 (ACSL4) and arachidonate 15-lipoxygenase (ALOX15), and reports relocation of an ACSL4-PKCβ-ALOX15 complex to lipid droplets during ferroptotic stress. These findings connect calcium dynamics to lipid metabolism through a spatially organized phosphorylation program. We propose that lipid droplets should not be classified as constitutively protective or pro-ferroptotic organelles. Instead, they may undergo a calcium-gated licensing transition: under basal or transient stress, neutral-lipid storage buffers polyunsaturated fatty acids; under sustained, spatially restricted calcium signaling, PKCβ-dependent phosphorylation may convert the lipid-droplet surface into a catalytic staging platform that supplies and oxidizes ferroptosis-sensitive lipids. This model explains why lipid-droplet biogenesis can suppress ferroptosis in one context but support it in another, and it predicts a relay from lipid droplets to endoplasmic-reticulum and endoplasmic-reticulum-mitochondria contact sites where phospholipid peroxidation can propagate. Distinguishing initiating calcium microdomains from late calcium influx through damaged plasma membranes will be essential. Phosphosite-resolved imaging, organelle-targeted calcium sensors, contact-site lipidomics, and tissue-specific perturbation of PKCβ should test this framework and may enable selective ferroptosis induction in cancer while preserving calcium-overloaded tissues such as the exocrine pancreas.

Keywords:  ACSL4; ALOX15; Calcium signaling; Ferroptosis; Lipid droplets; Organelle contact sites; PKCβ

DOI:  https://doi.org/10.1016/j.ceca.2026.103194
Soft Matter. 2026 Sep 17.

Topological defects mediate collective transport of confluent cells.

Jiusi Zhang, Chung Wing Chan, Bo Li, Rui Zhang.

Collective cell migration governs a range of physiological and pathological processes, from tissue morphogenesis to cancer invasion, in which topological defects arise as an inevitable consequence of frequent cellular rearrangement and migration. Here, we employ the active vertex model to investigate structural defects generated in the wake of transported cells. We find that while the drag coefficient of a cell in a perfect lattice is anisotropic, the threshold drag force required to mobilize the cell is isotropic. Remarkably, we find that dragging two neighboring cells along the direction of least resistance minimizes lattice disruption. By comparing defect-healing behaviors across different physical models, we disentangle the contributions of cell adhesion and many-body interactions. Together, our findings provide new insights into the topological organization of confluent tissues during collective migration, advancing our physical understanding of cellular transport processes such as wound healing, tissue repair, and cancer metastasis.

DOI: https://doi.org/10.1039/d6sm00296j
Cancer Cell. 2026 Sep 16. pii: S1535-6108(26)00389-2. [Epub ahead of print]

Chemotherapy-free phase 1/2 trial of HRS-4642 plus adebrelimab in previously treated metastatic KRAS G12D-mutant pancreatic cancer.

Si Shi, Miaoyan Wei, Nan Du, Jialin Li, Boyue Han, Wei Wang, Xin Hu, Fei Luo, Jin Xu, Xianjun Yu.

  KRAS G12D mutations drive approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and foster an immunosuppressive tumor microenvironment. This phase 1/2 trial (NCT06427239) evaluated HRS-4642, a selective KRAS G12D inhibitor, combined with the PD-L1 blockade adebrelimab in 48 pretreated patients with metastatic KRAS G12D-mutant PDAC. Dose escalation revealed no dose-limiting toxicities, establishing the recommended phase 2 dose (RP2D), and no treatment-related deaths occurred; hypercholesterolemia and anemia (each 50%) were the most common treatment-related adverse events. In the RP2D cohort (n = 37), the confirmed objective response rate was 43.2% (95% confidence interval [CI], 27.1-60.5), disease control rate was 81.1% (95% CI, 64.8-92.0), median duration of response was 6.9 months (95% CI, 4.8-8.6), median progression-free survival was 5.7 months (95% CI, 4.0-7.5), and median overall survival was 11.5 months (95% CI, 9.2-16.9). This chemotherapy-free regimen is tolerable and shows encouraging antitumor activity in refractory KRAS G12D-mutant PDAC, warranting further investigation.

Keywords:  HRS-4642; KRAS G12D; adebrelimab; pancreatic cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.ccell.2026.08.012
Nat Cell Biol. 2026 Sep 15.

Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.

Johannes Breithofer, Nermeen Fawzy, Clara Zitta, Martin Tischitz, Dominik Bulfon, Clemens Hofmann, Lennart Hartig, Carina Wagner, Gernot F Grabner, Anita Pirchheim, Achim Lass, Ulrike Taschler, Keira Turner, Kasparas Petkevicius, Ulrich Stelzl, Dagmar Kratky, Rolf Breinbauer, Robert Zimmermann.

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.

DOI: https://doi.org/10.1038/s41556-026-02059-8
Biochem Soc Trans. 2026 Sep 23. 54(9): 1309-1318

NINJ1: implications for plasma membrane rupture and disease.

Elliott M Bernard, Ella Hartenian.

  Cell death pathways are ancient strategies that maintain homeostasis and protect organisms from infection and injury. Lytic cell death culminates in the rupture of the plasma membrane, which was recently revealed to be driven by Ninjurin-1 (NINJ1), a plasma membrane protein that oligomerizes during cell death. NINJ1 oligomerization creates lesions in the plasma membrane that facilitate the release of cytosolic contents. In the present review, we discuss what is currently known about NINJ1 biology, focusing on the most current research into potential mechanisms of activation. We then highlight how NINJ1 has been implicated in specific disease contexts and discuss potential ways NINJ1 may contribute to disease. We conclude with the remaining open questions relating to NINJ1 biology.

Keywords:  Ninj1; cell death; immunology; inflammation

DOI:  https://doi.org/10.1042/BST20260711
Biochim Biophys Acta Rev Cancer. 2026 Sep 14. pii: S0304-419X(26)00177-0. [Epub ahead of print]1881(6): 189705

Metabolic matching shapes organ-specific metastasis.

Cristina Álvarez-Álvarez, Patricia Altea-Manzano.

  Metastasis is the leading cause of cancer-related mortality, yet the mechanisms driving organ-specific colonization remain incompletely understood. Increasing evidence suggests that metastatic success depends on a "metabolic match" between disseminated tumor cells and the microenvironment of the target organ. In this mini-review, we discuss how intrinsic metabolic programs inherited from the primary tumor interact with extrinsic factors such as nutrient availability, redox balance, extracellular matrix remodeling, and organ-resident cells to shape metastatic organotropism. We propose that the interplay between cancer cell metabolic plasticity and tissue-specific metabolic landscapes critically determines metastatic fitness and may uncover new therapeutic vulnerabilities.

Keywords:  Metabolic match; Metabolic plasticity; Metastasis; Metastatic organotropism; Organ-resident cells; Pre-metastatic niche; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189705
Cell. 2026 Sep 17. pii: S0092-8674(26)01013-5. [Epub ahead of print]189(19): 5825-5826

Evolving Cell with evolving science.

John W Pham.

DOI: https://doi.org/10.1016/j.cell.2026.08.040
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123

Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

  Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

Keywords:  SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling

DOI:  https://doi.org/10.1073/pnas.2616684123
Cancer Res. 2026 Sep 16.

A Stiff Achilles' Heel: How Tumor Mechanics Shape Metastatic Vulnerability.

Weilin Li, Li Tang.

Metastatic cancer cells must adapt to the physical properties of distant tissues, yet the consequences of such mechanical adaptation for immune surveillance remain poorly understood. In Immunity, Elbanna and colleagues reveal an unexpected trade-off between mechanical fitness and immune vulnerability: Environmental rigidity induces cancer-cell stiffening, enabling robust colonization of rigid bone in the absence of effective cytotoxic immunity. However, this mechanically adapted state also increases susceptibility to cytotoxic lymphocytes, allowing immunosurveillance to preferentially eliminate stiffened cancer cells and suppress bone metastasis in immunocompetent hosts. SPP1 contributes to this environmentally induced mechanical adaptation and its associated immune vulnerability. This study also highlights a broader mechanical dialogue between the metastatic niche, cancer cells, and the immune system, in which adaptation to one physical constraint may create vulnerability to another. Mechanistically, cancer-cell mechanics may represent more than a consequence of tumor progression-it may constitute an actionable determinant of immune susceptibility. Manipulating the mechanical state of cancer cells could therefore complement strategies aimed at enhancing immune-cell function. The study raises the intriguing possibility that the very adaptation that enables cancer cells to establish themselves within a rigid metastatic niche may simultaneously expose a therapeutically exploitable mechanical vulnerability to immune surveillance.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-3927
JAMA. 2026 Sep 18.

FDA Approves New Treatment for Advanced Pancreatic Cancer.

Samantha Anderer.

DOI: https://doi.org/10.1001/jama.2026.14719
Photoacoustics. 2026 Oct;51 100878

Real-time quality control in optoacoustic mesoscopy for enhancing data quality and standardization in clinical studies.

María Begoña Rojas López, Manuel Gehmeyr, Suhanyaa Nitkunanantharajah, Hubert Preißl, Andreas Vosseler, Reiner Jumpertz von Schwartzenberg, Andreas L Birkenfeld, Nikoletta Katsouli, Nikolina-Alexia Fasoula, Angelos Karlas, Michael Kallmayer, Daniela Branzan, Anette-Gabriele Ziegler, Dominik Jüstel, Vasilis Ntziachristos.

  Raster scan optoacoustic mesoscopy (RSOM) has matured as a medical imaging modality that enables unique high-resolution visualization of optical contrast at depths of several millimeters. Compared with other optical methods, optoacoustics is less affected by photon scattering, enabling superior imaging of dermatological, cardiometabolic, and other conditions. A critical requirement for clinical adoption is the development of methodology that ensures quality control and standardization across subjects, time points, and acquisition environments. We present a machine-learning-based automated real-time quality control method for RSOM using signal-derived metrics for noise and motion. The model was trained and evaluated on 1725 clinical RSOM scans benchmarked against visually perceived image quality ratings from eight experts. The method enables real-time feedback during acquisition to identify suboptimal scans and support standardized high-quality data acquisition. We discuss the impact of the method on clinical RSOM deployment, and the cost benefits achieved through data standardization.

Keywords:  Assessment; Cost; Evaluation; Motion; RSOM; Real-time; SNR

DOI:  https://doi.org/10.1016/j.pacs.2026.100878
Nat Commun. 2026 09 16. pii: 9877. [Epub ahead of print]17(1):

Quantitative proteomics reveals coordinated changes in the proteome during replicative senescence.

Nádia Da Silva Fernandes, Fridolin Kielisch, Amitkumar Fulzele, Sivarajan Karunanithi, Justus F Gräf, Jia-Xuan Chen, Christian Behl, Helle D Ulrich, Petra Beli.

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated manner, characterized by widespread protein depletion on chromatin. Moreover, components of the cytoplasmic translation machinery are depleted, while mitochondrial proteins display increased insolubility. Autophagic and proteasome activity is compromised in senescent cells along with remodeling of ubiquitin linkages and depletion of ubiquitin E3 ligases. Comparison of the senescent proteome with different pathophysiological cellular states reveals a distinctive senescent signature shaped by changes in the proteostasis network. Collectively, we provide a resource for the exploration of temporally resolved changes in the senescent proteome.

DOI: https://doi.org/10.1038/s41467-026-77686-8
Nat Cell Biol. 2026 Sep 15.

DFCP1-containing ER microdomains mediate lysosomal membrane repair.

Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.

Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.

DOI: https://doi.org/10.1038/s41556-026-02062-z
Cancer Lett. 2026 Sep 12. pii: S0304-3835(26)00587-2. [Epub ahead of print] 218823

Lack of tumor-derived LCN2 sensitizes pancreatic cancer cells to ferroptosis induction.

Valentina Pita-Grisanti, Kristyn Gumpper-Fedus, Claire Cornellier, Hsiang-Yin Hsueh, Grace Vulic, Zachary Hurst, Ericka Velez-Bonet, Kaylin Chasser, Olivia Harder, Andrew J Gunderson, Stacey Culp, Maciej Pietrzak, Amy Webb, Thais F Bartelli, Florencia McAllister, Zobeida Cruz-Monserrate.

  Lipocalin 2 (LCN2) is upregulated in many cancers, including pancreatic ductal adenocarcinoma (PDAC), and contributes to tumor development. LCN2 regulates microbial composition, which can influence PDAC outcomes, and has been implicated in ferroptosis resistance in several cancer types. However, the role of tumor-derived LCN2 in mediating ferroptosis and the tumor microbiome in PDAC remains unclear. Here, we show that human PDAC tumors with high LCN2 expression have altered expression of genes involved in ferroptosis, oxidative stress responses, and microbial regulation. Loss of LCN2 in PDAC cells dysregulates ferroptosis-associated pathways, increases lipid peroxidation, and sensitizes cells to ferroptosis induction. In orthotopic PDAC models, the ferroptosis inducer imidazole ketone erastin (IKE) promoted tumor growth in Lcn2-expressing tumors, whereas this effect was absent in tumors lacking LCN2. In addition, tumor-derived Lcn2 expression and ferroptosis induction were associated with distinct changes in the pancreatic tumor microbiome. Overall, these findings identify tumor-derived LCN2 as an important modulator of ferroptotic stress responses in PDAC and suggest that inhibition of tumor-derived LCN2 may enhance susceptibility to ferroptosis-based therapeutic strategies.

Keywords:  Lipocalin 2; ferroptosis; microbiome; pancreatic cancer

DOI:  https://doi.org/10.1016/j.canlet.2026.218823
Redox Biol. 2026 Sep 17. pii: S2213-2317(26)00405-2. [Epub ahead of print]97 104406

Decreased FSP1 expression under chronic hypoxia sensitizes human macrophages towards ferroptosis.

Anja Wickert, Anna Schwantes, Yara Shadid, Sofie P Meyer, Bernhard Brüne, Dominik C Fuhrmann.

  Ferroptosis, an iron-dependent cell death, emerged as a new therapeutic approach to treat diseases such as cancer or diabetes. Several pathological conditions are characterized by the appearance of chronic hypoxia, which is known to attract immune cells, especially monocytes and macrophages. Therefore, we investigated how chronic hypoxia affects ferroptosis in primary human macrophages and THP-1 cells. Chronic but not acute hypoxia sensitized cells towards ferroptosis, in line with elevated cellular as well as mitochondrial lipid peroxides, and mitochondrial ROS. Time kinetics revealed an earlier increase in lipid peroxidation under chronic hypoxia compared to normoxia, which was followed by mitochondrial lipid peroxidation and mitochondrial ROS. Mechanistically, and in contrast to normoxia and/or acute hypoxia, chronic hypoxia diminished nuclear abundance and activity of the antioxidant transcription factor NRF2. Consequently, NRF2 target gene expression, including ferroptosis suppressor protein 1 (FSP1), decreased. Inhibition or knockdown of FSP1 mimicked the ferroptosis-sensitizing effect of chronic hypoxia. To causatively link decreased NRF2 activity to increased ferroptosis under hypoxia, we inhibited KEAP1, which preserved NRF2 activity, increased FSP1 expression, and decreased ferroptosis. Our data provides novel insights into NRF2 regulation under chronic hypoxia linked to FSP1 expression and ferroptosis sensitivity of primary human macrophages.

Keywords:  AIFM2; Lipid peroxidation; NRF2; THP-1

DOI:  https://doi.org/10.1016/j.redox.2026.104406
Cells. 2026 Aug 25. pii: 1531. [Epub ahead of print]15(17):

Viscotaxis: An Emerging Driver for Directed Cell Migration.

Zijian Chen, Zhen Wang, Guanglin Wang.

  Directed cell migration orchestrates embryonic development, wound repair, immune surveillance and malignant tumor invasion. Viscotaxis-directed cell migration along spatial gradients of extracellular fluid viscosity or matrix loss modulus-has emerged as a candidate mechanotaxis modality that may guide cells through heterogeneous viscoelastic tissues; however, its biological functions and molecular underpinnings remain largely uncharacterized, and direct evidence in mammalian systems is still limited to a small number of studies. This mini-review first defines viscotaxis and distinguishes it from the related but physically different mechanical quantities with which it is frequently conflated-substrate stiffness, matrix viscoelasticity, and stress relaxation-and then summarizes its physiological and pathological relevance across development, tissue homeostasis, immunity, and cancer. We outline the putative multi-step mechanosensory cascade governing viscotactic responses, examine how viscotaxis may synergize or compete with durotaxis, haptotaxis, chemotaxis, electrotaxis, and phototaxis under mixed microenvironmental cues, and compare the distinct hydrodynamic and steric-exclusion mechanisms proposed across spiral microbes, flagellated eukaryotes, mammalian cells, and embryonic tissues. Throughout, we explicitly distinguish evidence obtained under viscosity gradients from that obtained under uniformly elevated viscosity and established findings from working hypotheses. Finally, we discuss current methodological bottlenecks and unresolved conceptual debates and propose biomaterial tools and therapeutic strategies to advance viscotaxis from a biophysical curiosity toward a core principle of cellular mechanobiology.

Keywords:  cell mechanics; directed cell migration; viscoelasticity; viscotaxis

DOI:  https://doi.org/10.3390/cells15171531
Front Big Data. 2026 ;9 1924721

GICPIdb: an archival repository of multimodal data focusing on pathological images for gastrointestinal cancers.

Huang Chen, Ling Tong, Jinyang Liu, Kai Liu, Xintao Li, Shufang Shi, Shuxue Xi, Geng Tian, Meijun Zhang, Dingrong Zhong, Shijun Li, Jialiang Yang.

   Introduction: Deep learning (DL) shows great potential for predicting biomarkers from routine histopathological slides of gastrointestinal (GI) cancers. Yet most existing models are validated on limited patient cohorts, while pathological image annotation and molecular marker standardization demand substantial professional expertise. To address these gaps, we constructed the Gastrointestinal Cancer Pathological Image Archive (GICPIdb, gicpidb.shubuzuo.top), a dedicated database and web platform covering seven major GI cancer types.
Methods: High-quality hematoxylin and eosin (H&E)-stained whole-slide images were collected from multiple sources and uniformly processed. Image annotations were performed by board-certified pathologists following standardized protocols. GICPIdb offers five interactive web modules for data uploading, quality control, feature extraction, online annotation and AI-based prediction. Its intuitive interface supports data browsing, retrieval, visualization and downloading.
Results: The database houses 2,863 pathologist-annotated, uniformly processed, high-quality H&E stained images collected from 2,655 patients. Of these, 1,699 patients were sourced from The Cancer Genome Atlas (TCGA), 182 from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and 424 from China-Japan Friendship Hospital and 350 from Chifeng Municipal Hospital in Inner Mongolia, China. It also integrates data on over 50 key molecular markers (e.g., MSI, TMB) and prognostic labels related to survival, recurrence and metastasis.
Discussion: GICPIdb aims to promote the development of DL-driven AI tools for cancer research and clinical translation. The multi-institutional data collection and standardized annotation pipeline are expected to enhance the generalizability and reproducibility of AI-based prediction models across diverse patient populations.

Keywords:  deep learning; gastrointestinal cancers; molecular biomarker; multimodal data; pathological image

DOI:  https://doi.org/10.3389/fdata.2026.1924721
Trends Cancer. 2026 Sep 15. pii: S2405-8033(26)00207-4. [Epub ahead of print]

Lkb1 loss links dietary lipids to cancer cachexia.

Xiaolin Liu, Jiayi Shen, Gaofei Wei.

  Cancer cachexia involves more than a caloric deficit. A recent study by Cross et al. in Science shows that dietary lipid composition exacerbates cachexia in LKB1/STK11-deficient lung cancer through local prostaglandin E2 production and pulmonary sensory neuron activation. By linking local lipid metabolism to anorexia and wasting, these findings support precision nutritional interventions for cancer cachexia.

Keywords:  Lkb1/Stk11 deficiency; PGE(2); cancer cachexia; dietary lipid; sensory neurons

DOI:  https://doi.org/10.1016/j.trecan.2026.08.011
iScience. 2026 Sep 18. 29(9): 117352

R0 Resection improves survival after multivisceral resection for pancreatic ductal adenocarcinoma.

Multivisceral Pancreatic Resections Research Group: A Collaboration of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA)

  Achieving negative resection margins (R0) is central to curative surgery for pancreatic ductal adenocarcinoma (PDAC), but its prognostic relevance in multivisceral resections has been unclear. Using the largest international registry of multivisceral pancreatic resections, we performed a propensity score-matched analysis comparing R0 and R1 resections in patients undergoing multivisceral resection for PDAC. After 1:1 matching on pre- and intra-operative covariates, 222 patients were analyzed (111 R0, 111 R1). Perioperative morbidity, 90-day mortality, and intraoperative complications were comparable between groups. Median overall survival was 22.3 months after R0 resection versus 14.5 months after R1 resection; R1 status remained independently associated with poorer survival after adjustment for residual imbalances (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.02-2.07). Margin-negative resection is associated with improved long-term survival in multivisceral pancreatic surgery without an accompanying increase in perioperative risk, supporting R0 resection as a goal of surgical strategy at specialized centers.

Keywords:  multivisceral; pancreatic; surgery

DOI:  https://doi.org/10.1016/j.isci.2026.117352
FEBS Open Bio. 2026 Sep 15.

Type I interferons modulate autophagy to shape gemcitabine response in pancreatic cancer cells.

Lucy E Bonilla, Martín M Ledesma, Santiago A Behr, Matías A Pibuel, María L Palanek, Daniel H Grasso, Maria N Garcia, Juan Garona, Silvina L Lompardía, Elida Álvarez, Daniela L Papademetrio.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by poor prognosis and limited response to gemcitabine, the standard first-line chemotherapy. One major contributor to chemoresistance is autophagy, a process frequently upregulated in PDAC. In this study, we examined the ability of type I interferons (IFNα2b and IFNβ1a) to modulate autophagy and disturb tumor cell resistance to gemcitabine. PDAC cells were treated with increasing concentrations of IFNα2b or IFNβ1a, and cell proliferation was assessed by [3H]-thymidine incorporation. Apoptosis was evaluated by TUNEL staining following treatments with interferons and/or gemcitabine. STAT1 phosphorylation was analyzed as a marker of downstream type I interferon signaling. Autophagy was analyzed by western blot for LC3B, Beclin-1, Bcl-XL and p62/SQSTM1, and by quantifying autophagic flux using mCherry-EGFP-LC3B-transfected cells in the presence or absence of lysosomal inhibitors. We found that IFNα2b promoted autophagic flux and reduced gemcitabine-induced cell death, indicating a cytoprotective role. In contrast, IFNβ1a reduced autophagosome formation and significantly enhanced cell death, without clear evidence of altering autophagic flux. Both interferons induced STAT1 phosphorylation, confirming engagement of downstream type I interferon signaling. Our findings highlight the contrasting roles of IFNα2b and IFNβ1a in the regulation of autophagy and gemcitabine response and suggest that IFNβ1a, by reducing autophagosome formation, may sensitize PDAC cells to chemotherapy. These findings identify IFNβ1a as a potential chemosensitizing agent in PDAC and provide a rationale for further evaluating combinations of IFNβ1a, gemcitabine, and autophagy-targeting strategies to overcome chemoresistance.

Keywords:  IFNα2b; IFNβ1a; autophagy; chemoresistance; gemcitabine; pancreatic cancer

DOI:  https://doi.org/10.1002/2211-5463.70342
Nat Cancer. 2026 Sep 11.

MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.

Peixiang Zheng, Yanni Lin, Meiyin Zhang, Zhiyuan Tang, Wenxing Qin, Min Xiao, Xue Sun, Yuli Shen, Zhiqiang Hu, Shuo Ru, Yuran Duan, Bofei Dong, Ting Wen, Mengdie Li, Hong Wu, Yueru Hou, Guimei Ji, Zheng Wang, Xiaohong Wu, Qimin Zhou, Xiaoguang Liu, Gaopeng Li, Yuhao Wang, Shengzhong Duan, Yang Luo, Bo Chu, Xu Qian, Zhimin Lu, Yuan Ding, Chuan Xu, Xu Qian, Tong Liu, Daqian Xu.

Limited efficacy of neoadjuvant chemotherapy (NAC) in pancreatic ductal adenocarcinoma (PDAC) underscores the need for novel combination strategies and a deeper understanding of metabolic determinants of chemoresistance. Here we identify methylmalonate semialdehyde dehydrogenase (MMSDH), a valine catabolism enzyme, as a driver of gemcitabine (GC) resistance. Hypoxia induces GCN5-mediated lactylation of MMSDH at K113. Lactylated MMSDH interacts with acyl-CoA synthetase long-chain family member 4 (ACSL4), generating propionyl-CoA to facilitate KAT8-mediated ACSL4 K606 propionylation. This modification enhances ACSL4-HSC70 binding, promoting its degradation through chaperone-mediated autophagy. Critically, this MMSDH-mediated ACSL4 propionylation correlates with low ACSL4 levels and poor NAC response in recipients. Combining dietary valine restriction with GC synergistically induces ferroptosis and suppresses tumor growth. Blocking MMSDH-K113la disrupts this axis, potentiating GC-induced ferroptosis and inhibiting tumor progression. These findings reveal a previously unknown mechanism of ferroptosis evasion through valine metabolism and ACSL4 regulation, nominating the GCN5-MMSDH-ACSL4 axis as a therapeutic target to enhance PDAC chemosensitivity.

DOI: https://doi.org/10.1038/s43018-026-01236-w
Nat Cancer. 2026 Sep 14.

Targeting valine metabolism and ferroptosis to overcome chemoresistance in PDAC.

DOI: https://doi.org/10.1038/s43018-026-01235-x
Trends Open. 2026 Sep;1(3): 215-226

T cells are blind to the dark mechanics of tumors.

Marco Fritzsche, Karsten Kruse.

  Tumor mechanics differ profoundly from those of healthy tissues. Yet, how abnormal mechanical properties affect T cell activation remains largely unresolved. In this opinion article, we propose that the aberrant mechanical landscape of cancer cells directly undermines early T cell activation. Substantiated by theory, we demonstrate that the lifetime of the T cell receptor-antigen bond critically depends on target cell elasticity and viscosity. By altering their viscoelastic properties, cancer cells can escape the mechanosensitive window required for T cell signaling, rendering themselves immunologically invisible. We term this phenomenon 'dark mechanics', a process where tumors exploit physical traits to subvert antigen discrimination, creating a mechanical route of immune evasion. This discussion suggests an opportunity to mechanically illuminate tumors for next-generation immunotherapies.

Keywords:  T cell receptor; cancer; catch–slip bond; dark mechanics; force

DOI:  https://doi.org/10.1016/j.treopn.2026.05.007
Cell Chem Biol. 2026 Sep 17. pii: S2451-9456(26)00289-8. [Epub ahead of print]33(9): 1252-1269.e5

Nitrated fatty acids form membrane biochemical capacitors that restrain inflammation.

Nicole Colussi, Sonia R Salvatore, Matias M Vazquez, Maria V Gutierrez, Scott Hahn, Karina Ricart, Felipe Vendrame, Matias Badino, Agustina L Schopfer, Dario A Vitturi, Luis Villacorta, Rakesh P Patel, Amit Gaggar, Carsten Skarke, Adam C Straub, Francisco J Schopfer.

  Nitrated fatty acids (NO2-FAs) are electrophilic lipid mediators that suppress inflammatory signaling, yet the sources, storage mechanisms, and physiological functions of endogenous NO2-FAs remain poorly understood. Here, we identify nitro-conjugated linoleic acid (NO2-CLA) as a diet-derived anti-inflammatory lipid that accumulates in membrane phospholipids and functions as a mobilizable biochemical reserve. Using cellular, murine, and human models, we show that phospholipids store NO2-CLA under basal conditions and rapidly release it during inflammatory stress through phospholipase-dependent remodeling. Mobilized NO2-CLA dampens cytokine production, limits inflammatory mediator formation, and preserves vascular homeostasis during endotoxemia. In both experimental inflammation and human sepsis, tissue and circulating pools of NO2-CLA become depleted, indicating that consumption exceeds endogenous replenishment during acute inflammatory responses. These findings establish membrane phospholipids as reservoirs of endogenous NO2-FAs and reveal a previously unrecognized mechanism by which diet, lipid metabolism, and redox signaling converge to regulate inflammation.

Keywords:  anti-inflammatory; conjugated linoleic acid; endotoxemia; lipid mediator; nitrated fatty acids; phospholipids

DOI:  https://doi.org/10.1016/j.chembiol.2026.08.002
iScience. 2026 Sep 18. 29(9): 117479

ARNTL2 promotes metastatic phenotypes through SERPINE1 transcription in KRAS G12D pancreatic cancer.

Xiaohan Shi, Xiaoyi Yin, Suizhi Gao, Xinqian Wu, Huan Wang, Beilei Wang, Xiongfei Xu, Kailian Zheng, Wei Jing, Gang Li, Shiwei Guo, Gang Jin.

  Despite the prevalence of the KRAS G12D mutation in approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and its association with the poorest prognosis among KRAS variants, the downstream transcriptional effectors driving its aggressive metastatic phenotype remain poorly defined. Through integrated bioinformatics and experimental validation, we identified ARNTL2 as a factor associated with KRAS G12D-mutant PDAC. ARNTL2 directly bound to the SERPINE1 promoter to activate its expression, establishing an ARNTL2-SERPINE1 axis that orchestrated epithelial-mesenchymal transition and drove metastasis in vitro and in vivo. Rescue experiments confirmed SERPINE1 as the indispensable downstream mediator. Clinical validation demonstrated that ARNTL2 and SERPINE1 protein levels correlated positively and stratified patients into distinct prognostic subgroups. Furthermore, this axis altered sensitivity to selective KRAS G12D inhibition in vitro. These findings identify an experimentally supported ARNTL2-SERPINE1 transcriptional axis in KRAS G12D-mutant PDAC that warrants further validation in genotype-faithful and clinically relevant models.

Keywords:  ARNTL2; KRAS G12D mutation; SERPINE1; epithelial-mesenchymal transition; metastasis; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.isci.2026.117479
J Biomed Res. 2026 Sep 25. 1-18

Exercise as a multisystem signaling therapy: A hypothesis integrating inter-organ communication and membrane microdomain regulation in metabolic disease.

Ella Zhang, Wei Zheng Zhang.

  Exercise is a powerful non-pharmacological intervention for metabolic diseases, yet current mechanistic explanations remain fragmented across individual organs. This review proposes that exercise may act as a multisystem signaling therapy, generating interdependent mechanical, endocrine, metabolic, inflammatory, and redox cues that integrate communication among skeletal muscle, adipose tissue, liver, endothelium, and the central nervous system. We introduce a conceptual model in which caveolae, cholesterol-rich membrane microdomains formed by caveolins and cavins, serve as a spatial platform that helps cells interpret and integrate these diverse extracellular signals into unified intracellular responses. Evidence already supports caveolar roles in mechanotransduction, insulin receptor organization, lipid handling, nitric oxide signaling, and membrane tension buffering. However, direct causal links between exercise-induced caveolar remodeling and whole-body metabolic adaptation remain limited. Rather than positioning caveolae as the sole regulator of exercise responses, this review synthesizes current findings across tissues, differentiates established mechanisms from emerging hypotheses, and evaluates how exercise modality, tissue context, and metabolic disease states may shape caveolae-dependent signaling. We outline experimental strategies capable of testing this framework and highlight key gaps that must be addressed before caveolae-targeted interventions can be translated clinically. By integrating systems physiology with membrane biology, this review provides a mechanistically grounded and testable model for understanding how exercise coordinates metabolic homeostasis through spatial regulation of cellular signaling.

Keywords:  caveolae; exercise; exercise therapy; exerkines; mechanotransduction; membrane microdomains; metabolic disease; systems physiology

DOI:  https://doi.org/10.7555/JBR.40.20260331
Lab Anim (NY). 2026 Sep 11.

Activating a patient-relevant pathogenic variant of a genetically defined heart disease in a humanized pig model.

Petra Runa-Vochozkova, Michaela Vaskovicova, Josep M Cambra, Andrea Bähr, Eva-Maria Männer, Mayuko Kurome, Valeri Zakhartchenko, Tuna Güngör, Barbara Kessler, Heinke C Heymer, Mara L Corsten, Tarik Bozoglu, Vijayanand Rajendran, Solomon K Yator, Tatjana Dorn, Jessica K Hernandez, Ina M Luksch, Magdalena Harakalova, Peter van Tintelen, Stefan Juhas, Jana Juhasova, Carolina G Cabrera-Gómez, Susanne Zöls, Steffanie Senf, Francesca Stillitano, Joost P G Sluijter, Mathias Ritzmann, Zdenka Ellederova, Motlik Jan, Pieter A Doevendans, David Drutovic, Pieter C Glijnis, Eckhard Wolf, Christian Kupatt, Nikolai Klymiuk.

Complex diseases such as progressive cardiomyopathies are often insufficiently recapitulated in small animals or in vitro models. Large animal species such as pigs provide a valuable alternative, but constitutive genetic manipulation has not yet been applied to pigs in an effective manner, mainly due to biological and logistical limitations. Here we describe the generation of a humanized pig model for phospholamban-mediated cardiomyopathy and compare different methods for activating a pathogenic R14del mutation by Cre-mediated recombination. Both Cre treatment of pig primary cells before somatic cell nuclear transfer as well as microinjection of Cre-encoding mRNA into zygotes were similarly efficient in delivering piglets with an activated R14del mutation. Alternatively, administration of Cre-encoding adeno-associated virus into piglets was sufficient, albeit to a varying extent. Together, we describe a highly effective process to establish complex inducible genetic traits in pig and demonstrate that the lack of Cre-driver lines can be compensated by various interventions during reproduction or postnatally.

DOI: https://doi.org/10.1038/s41684-026-01787-6
Nat Methods. 2026 Sep 14.

CFM: confinement force microscopy-a dynamic, precise and stable microconfiner for traction force microscopy in spatial confinement.

Fatemeh Abbasi, Katharina Rieck, Matthias Brandt, Maja Matis, Eva Kiermaier, Timo Betz.

Cells migrating through tissues experience changing physical confinement, yet methods to dynamically control confinement while quantifying the resulting forces remain limited. Here we present a microconfiner platform for live-cell imaging that enables programmable confinement, allowing real-time control over the level, timing and frequency of confinement while measuring traction forces exerted on the microenvironment, a method we term confinement force microscopy (CFM). Using CFM, we find that cells respond to confinement in two phases: a rapid passive stress rise caused by compression of the cell body and nucleus against the substrate, followed by an active stress increase associated with enhanced contractility, intracellular pressure buildup and bleb formation. Bleb expansion can partially relieve pressure and reduce stress on the surroundings. ROCK and myosin II inhibition both reduce stress generation, but with distinct effects on blebbing. Overall, CFM provides a versatile approach to study dynamic mechanical adaptation in tissue-like environments.

DOI: https://doi.org/10.1038/s41592-026-03216-5
Protein Sci. 2026 10;35(10): e70786

DisPhaseDB 2.0: Improved interpretation of disease-associated variants in liquid-liquid phase separation proteins with agent-accessible querying.

Justo Garcia-Messina, Alvaro M Navarro, Cristina Marino-Buslje.

  Membraneless organelles formed through liquid-liquid phase separation (LLPS) are fundamental to cellular organization and are involved in multiple processes, including responses to stimuli and stress. The study of disease-associated variants in LLPS proteins remains vital for understanding protein dysfunction in human diseases. However, maintaining specialized, integrative resources is often hindered when database updates rely on human intervention, typically resulting in long intervals between updates. Here, we introduce a major update to DisPhaseDB (https://disphasedb.leloir.org.ar/), a comprehensive resource for disease-associated variants in LLPS proteins, integrated with an open-source Snakemake workflow organizing systematic data acquisition and parsing into traceable steps. Crucially, the automated system continuously fetches data from source databases, keeping DisPhaseDB up-to-date without the delays of manual maintenance. The updated release expands the database with additional proteins, increases disease annotation coverage by 174%, and adds clinical significance and allele frequency annotations to enhance variant interpretation. To improve accessibility, we also introduce a Model Context Protocol (MCP) server that establishes a standardized interoperability layer, enabling AI agents and large language models to directly query database records through structured operations. This architecture grounds generative workflows in a trusted source, replacing unconstrained web retrieval and reducing unsupported content. In a comparative benchmark, data retrieval through the MCP server achieved a mean F1 score of 0.99, compared to 0.30 for unguided generative retrieval. Together, these developments position DisPhaseDB2.0 as a maintainable resource for LLPS-related variants, optimizing reproducible data access for both human researchers and emerging agentic AI workflows.

Keywords:  AI‐accessible; database; disease variants; liquid–liquid phase separation; membraneless organelles; model context protocol

DOI:  https://doi.org/10.1002/pro.70786
Comput Biol Med. 2026 Sep 14. pii: S0010-4825(26)00503-2. [Epub ahead of print]215 111937

Analyzing model inaccuracy and relative importance of parameters of discrete model of adhesion of circulating tumor cells for investigating metastatic dynamics.

Nahid Rahmati, Nima Maftoon.

  Metastasis is strongly influenced by the ability of cancerous cells to adhere to endothelial cells, facilitating their extravasation to distant organs; however, how uncertainty in cellular and adhesion properties propagates to observable dynamics remains unclear. A key finding is that a physiological "speed limit" imposed by Poiseuille flow fundamentally constrains this uncertainty: although input variability reaches a coefficient of variation (CV) of 20%, the resulting variability in CTC velocity saturates at ∼12%, revealing a bounded, nonlinear response rather than a linear error amplification. Coupling the stochastic LBM-DEM-IBM adhesive dynamic model with a high-fidelity Random Forest surrogate enables time-resolved global sensitivity analysis (Sobol' and E-FAST). This coupled model shows that parameter importance is stage-dependent: early attachment is dominated by membrane/link elasticity, whereas stable rolling is governed by bond spring stiffness and rupture mechanics. These insights explain why velocity variability attenuates while adhesion outcomes can still diverge (rolling vs detachment). In contrast, adhesion behavior remains highly sensitive to parameter variability. Machine learning (XGBoost) enables accurate classification of CTC rolling or detachment states with 95.62% accuracy, providing a predictive framework for assessing detachment likelihood under uncertainty. Together, these results establish a unified physics-to-mechanism perspective in which flow-imposed limits, stage-dependent control, and sparse parameter interactions govern CTC adhesion dynamics to enhance predictive models for metastasis.

Keywords:  Cell adhesion modeling; Global sensitivity analysis; Hemodynamics; LBM–DEM–IBM; Machine learning; Metastasis dynamics; Uncertainty quantification

DOI:  https://doi.org/10.1016/j.compbiomed.2026.111937
Cell. 2026 Sep 14. pii: S0092-8674(26)01004-4. [Epub ahead of print]

Programmed ribosomal frameshifting triggers translational stress to promote viral replication.

Audrey Xavier, Melinda Kolling, Ashley M Bourke, Thorsten Mosler, Cristian Prieto-Garcia, Emil Karaulanov, Michaela Reissland, Michel Tassetto, Damian Kim, Katleen Klaassen, Katharina Grikscheit, Emma Torbica, Verena Dederer, Jonas Busam, Rubina Kazi, Ruth Olmer, Srinivas Reddy Pallerla, Sebastian Mathea, Markus E Diefenbacher, Kathi Zarnack, Denisa Bojkova, Marek Widera, Ranen Aviner, Raul Andino, Sandra Ciesek, Ivan Dikic.

  Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.

Keywords:  RNA virus; cellular stress; host-pathogen interactions; integrated stress response; programmed ribosomal frameshifting; ribosome collision; translation; virology

DOI:  https://doi.org/10.1016/j.cell.2026.08.031
Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.

  The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Keywords:  GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling

DOI:  https://doi.org/10.1016/j.cell.2026.08.037
PLoS Comput Biol. 2026 Sep 18. 22(9): e1014750

Balanced contractility and adhesion drive polarization in a minimal elastic actomyosin network.

Zeno Messi, Franck Raynaud, Nathan W Goehring, Alexander B Verkhovsky.

Polarization of migrating cells involves chemical and mechanical interactions of signaling networks, cytoskeleton, plasma membrane, and substrate adhesions. Still, it is not fully understood which mechanisms and components are sufficient for symmetry breaking, and if they work independently or together. Here, we use a discrete active network model to investigate if and how an elastic cytoskeletal network is capable of breaking symmetry solely through mechanical interactions. Our minimal model consists of elastic bonds, attractive force dipoles, and force-sensitive anchor points, initially distributed uniformly and subject to simple turnover rules. We find that these features are sufficient to produce different cell behaviors, and, remarkably, to drive symmetry breaking and directed (polarized) motion. Network behavior was primarily determined by the turnover rate of anchor points, which, itself, is a function of the ratio between dipole force and the threshold force required for anchor removal. Directional motion emerged at intermediate turnover rates, at which tension in the network accumulated through several turnover cycles before eventually exceeding the adhesion removal threshold locally at the edge, mirroring our recent experimental findings on the correlation of the traction force with protrusion-retraction transitions in the cell. At high turnover rates, forces were unable to build up to sufficiently high levels, while at low turnover rates, anchors hindered motion. These results demonstrate how directed motion can emerge as an intrinsic property of a simple mechanical network, independently of external cues or complex signaling networks. Given the concordance between this model and recent experimental findings, we suggest that polarization by contraction-adhesion dynamics could be a fundamental emergent behavior of actin-myosin networks.

DOI: https://doi.org/10.1371/journal.pcbi.1014750
Prog Biophys Mol Biol. 2026 Sep 18. pii: S0079-6107(26)00068-4. [Epub ahead of print] 101951

Biophysical and molecular determinants of NCOA4-mediated ferritinophagy at the ferroptosis-inflammation interface: Compartmental iron transport, lipid oxidation, and causal constraints.

Rabab S Hamad, Marwa S Zaghloul, Ahmed Shata, Doaa N Abdallah, Alshaimaa H Abd Elmaksoud, Sherihan I Gouda, Nesreen Elsayed Morsy, Shereen Hamed, Sameh Saber.

  Ferritinophagy links molecular recognition of ferritin to the redistribution of redox-active iron across intracellular compartments. This critical narrative review examines nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy as a multiscale process in which NCOA4-FTH1 binding and ferritin condensation govern cargo organization, TAX1BP1-dependent trafficking controls lysosomal delivery, ferric reduction and ferrous export determine iron speciation and transport, and membrane composition and antioxidant kinetics set the threshold for ferroptotic lipid peroxidation. This biophysical-molecular perspective asks which spatially and temporally resolved steps have been demonstrated within the same experimental system. The strongest evidence supports NCOA4-dependent ferritin trafficking and degradation as a regulated source of bioavailable iron and a context-dependent determinant of ferroptotic competence. Evidence for a conserved downstream NCOA4-to-NLRP3 pathway is substantially weaker and remains model-dependent. Ferritinophagy-associated injury can instead yield cell-autonomous inflammasome activation, non-inflammasome signaling such as cGAS-STING activation, or intercellular transfer between parenchymal, immune, and stromal cells. We distinguish sequential cell-autonomous, parallel-convergence, and tissue-level/intercellular models rather than assuming a single linear axis. A study-level evidence map and causal-validation framework specify the measurements needed to connect these scales: ferritinophagy flux, compartment-resolved iron, lipid-peroxidation kinetics, selective ferroptosis rescue, lysosomal integrity, complete inflammasome outputs, temporal ordering, restoration, and cell-type localization. The central unresolved problem is when ferritin-derived iron becomes an execution-relevant, membrane-proximal pool and whether inflammatory signaling is coupled in the same cell or through intercellular transfer.

Keywords:  Biomolecular condensates; Ferritinophagy; Ferroptosis–inflammation coupling; Lysosomal iron transport; Membrane lipid peroxidation; NCOA4

DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.101951
Sci Adv. 2026 Sep 18. 12(38): eaei8554

Broadband backscattering confocal microscopy enables label-free 3D live cell nanoscale sensitive imaging.

Mark F Coughlan, Lei Zhang, Rebecca T Perelman, Umar Khan, Xuejun Zhang, Paul K Upputuri, Yuri N Zakharov, Le Qiu, Lev T Perelman.

Fluorescence microscopy is a cornerstone of biological research. However, fluorescent labeling is challenging in live cells and is constrained by photobleaching and phototoxicity. Label-free methods allow cells to be studied in their native state, but most techniques have poor contrast, lack 3D capability, rely on complex optics, or fail to provide structural information. We present here broadband backscattering confocal microscopy (BBCM), which employs a broadband supercontinuum laser and collects backscattered light in a confocal geometry using a photomultiplier tube. Broadband illumination averages out size-dependent oscillations that confound monochromatic backscattering. This eliminates blind spots and intensity ambiguities, allowing all scatterers to be visible, with the signal increasing approximately linearly with scatterer size. BBCM is easy to retrofit to standard confocal microscopes, requires no specialized optics, and is straightforward for nonspecialists. It enables high-contrast, label-free 3D imaging of live cells with size sensitivity to subcellular structures without employing custom optics or complex data processing.

DOI: https://doi.org/10.1126/sciadv.aei8554