bims-ginsta 2026-03-08 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–03–08
forty-two papers selected by
Jinrong Hu, National University of Singapore

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
Intracellular buffering enables developmental robustness after genome doubling in C. elegans embryos.
Multiscale mechanisms driving tissue rupture by invading cells.
Precancerous niche remodelling dictates nascent tumour persistence.
The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis.
RNA-specific local translation is patterned by condensates for multinucleate cell growth.
Function and regulation of the mitochondrial stress response.
Ventricular assist device unloading reverses microvascular senescence in single ventricle disease.
STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
Epithelial cell plasticity in metazoans: Evolutionary insights into roles and mechanisms.
Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.
Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.
Acidic niche sugar shield blocks ferroptosis.
Accessory subunits of PRC2 mimic H3K27me3 to restrict the spread of Polycomb domains.
DNA double-strand break response at a glance.
Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes.
Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.
A proteome-wide dependency map of protein interaction motifs.
Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs.
Global profiling of nascent chain interactors reveals TRIM25 as a co-translational E3 ubiquitin ligase.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
Single-cell chromatin accessibility landscape of cardiac non-myocytes identifies tissue repair program during heart regeneration.
The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.
Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.
Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.
Self-clustering of three CBX2 molecules drives PRC2 to promote facultative heterochromatinization of Polycomb target genes.
Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.
Genetically encoded assembly recorder temporally resolves cellular history.
Cell-free chromatin state tracing reveals disease origin and therapy responses.
The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
Compressive stress-driven Piezo1 activation and Rho-ROCK mechanotransduction promote tumor progression via epigenetic mechanical memory.
Attenuation of epicardial activation and myofibroblast abundance via the Fbln2-Nupr1b axis stimulates cardiac regeneration in zebrafish.
BCDX2-CX3 and DX2-CX3 complexes assemble and stabilize RAD51 filaments.
Loss of Splicing Homeostasis as a Hallmark of Aging.
GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.
Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation.
Piezo1-dependent activation of stromal cells ignites muscle inflammation in exercise and injury and is associated with inflammaging.
Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium.
Aurora B kinase phosphorylates keratin 8 at the cleavage furrow to drive spatially restricted intermediate filament disassembly during cytokinesis.
Senescence-related myocardial dysfunction: keeping a young heart.

Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Cell Rep. 2026 Mar 02. pii: S2211-1247(26)00083-5. [Epub ahead of print] 117005

Intracellular buffering enables developmental robustness after genome doubling in C. elegans embryos.

Miaoling Yang, Yuchuan Bai, Ziyi Wang, Zhuo Du.

  Whole-organism polyploidy is widespread across species, yet how embryogenesis adapts to genome doubling remains unclear. Here, we present a systematic single-cell comparison of embryogenesis between de novo-induced tetraploid and diploid C. elegans embryos, integrating live imaging, lineage tracing, phenotypic quantification, and transcriptomic profiling. Despite elevated transcript levels, slower proliferation, and altered cell architecture, tetraploid embryos develop with high fidelity, producing cell numbers, lineage patterns, fate specification, and tissue morphogenesis virtually indistinguishable from diploids. In tetraploids, transcriptional output increases proportionally with cell volume, resulting in largely stable transcript concentrations, although specific gene sets show divergence, suggesting additional layers of regulation. The importance of this scaling is underscored by their heightened sensitivity to size perturbations. Meanwhile, a sublinear volume increase relative to genome content raises DNA-to-volume ratios, correlating with delayed proliferation, suggesting potential physical or regulatory constraints on volume expansion. Our findings reveal how intracellular scaling strategies support accurate embryogenesis following genome doubling.

Keywords:  C. elegans; CP: developmental biology; CP: genomics; cell cycle; cell lineage; cell size; developmental robustness; embryogenesis; gene expression; polyploidy; single-cell analysis; tetraploid

DOI:  https://doi.org/10.1016/j.celrep.2026.117005
Dev Cell. 2026 Mar 04. pii: S1534-5807(26)00039-0. [Epub ahead of print]

Multiscale mechanisms driving tissue rupture by invading cells.

Selwin K Wu, Fuqiang Sun, Celestine Z Ho, Yuting Lou, Christina Bao-Xian Huang, Mui Hoon Nai, Jingwei Xiao, Murat Shagirov, Jasmine Fei Li Chin, Diana Lim, Suzie Verma, David S P Tan, Philippe Marcq, Alpha S Yap, Chwee Teck Lim, Tetsuya Hiraiwa, Yuan Lin, Boon Chuan Low.

  Cells migrate and invade tissues during development, immune responses, and cancer. Collective invasion is generally understood to be driven by invading cells unjamming and pushing through barriers such as the extracellular matrix and surrounding tissues. Whether these barriers actively contribute to invasion remains unclear. Using ovarian adenocarcinoma spheroids invading mesothelium derived from benign pleural effusions as an experimental model, combined with modeling, we examine invasion across molecular to multicellular scales. We identify intercellular integrin adhesions linking invasive leader cells to the tissue barrier, triggering apical constrictions within the barrier. This constriction shrinks cell-cell contacts, leading to barrier rupture. Thus, the tissue barrier plays a mechanically active role in invasion. Rather than cells pushing through, we find that coordinated subcellular contractility between the invading leader cell and the barrier drives barrier tensile rupture and invasion, independent of a jamming transition. Together, our findings challenge prevailing paradigms of collective cell invasion.

Keywords:  E-cadherin; active wetting; apical constriction; collective cell invasion; integrin adhesion; jamming transition; ovarian cancer metastasis; phase transition; tensile fracture; tissue mechanics

DOI:  https://doi.org/10.1016/j.devcel.2026.01.016
Nature. 2026 Mar 04.

Precancerous niche remodelling dictates nascent tumour persistence.

G Skrupskelyte, J E Rojo Arias, H Ajith, Y Dang, D Rossetti, S Han, M K S Tang, M T Bejar, B Colom, J C Fowler, K Murai, W Knight, D Aust, M H H Schmidt, J Jászai, S Zeki, A Noorani, P H Jones, S Rulands, B D Simons, M P Alcolea.

Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1-3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.

DOI: https://doi.org/10.1038/s41586-026-10157-8
Nat Struct Mol Biol. 2026 Mar 02.

The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis.

Jinhong Li, Yuechao Lu, Zhili Xia, Pengliang Chi, Qianqian Qi, Sibei Liu, Sicheng Ju, Jialu Li, Zihan Zhang, Zhuo Han, Qingting Liu, Wenbo Meng, Jing Chen, Xiang Wang, Li Guo, Lei Li, Wei Huang, Lunzhi Dai, Junhong Han, Shaorong Gao, Dong Deng.

Proteostasis in mammalian oocytes is vital for successful reproduction. The cytoplasmic lattices (CPLs) of oocytes store essential maternal proteins for early embryo development. Here we show that PADI6, a core component of CPLs, forms a conserved ternary complex that we term MPU for maternal PADI6-UHRF1-UBE2D. The MPU complex regulates protein ubiquitination during oocyte maturation and early embryogenesis. We determined the cryo-electron microscopy structure of MPU and show that 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly, revealing a potential molecular mechanism linking dysregulation of ubiquitination on oocytes to abnormal embryonic development. Mechanistically, PADI6, with the assistance of UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to relevant substrate proteins, thereby suppressing the ubiquitination cascade. Therefore, our findings implicate PADI6 in the regulation of proteostasis by controlling the ubiquitination cascade, expanding our understanding of PADI6-dependent regulation of oocyte maturation and early embryogenesis.

DOI: https://doi.org/10.1038/s41594-026-01758-y
Nat Cell Biol. 2026 Mar 02.

RNA-specific local translation is patterned by condensates for multinucleate cell growth.

Zachary M Geisterfer, Ameya P Jalihal, Sierra J Cole, Amy S Gladfelter.

Coordination between growth and nuclear division is a common cell feature. In some syncytia, nuclei divide asynchronously throughout the cell but growth occurs only at discrete locations, raising the question how the processes are locally regulated and globally coordinated. In the syncytial fungus Ashbya gossypii, both cell cycle progression and hyphal elongation require condensates formed by the protein Whi3 in complex with distinct mRNA species. Here we show that Whi3 condensates are enriched for translation regulators and are associated with local, spatially patterned translation of specific target RNAs near nuclei and growth sites. Whi3-RNA condensates can both promote and repress mRNA translation in an RNA- and condensate size-dependent manner in vitro. Condensate interfaces are sites of translation, tunable by condensate composition, RNA valency and protein charge state in vitro. Together, these data suggest that Whi3 condensates can generate a continuum of translation states that vary depending on the subcellular location and resident RNA sequences.

DOI: https://doi.org/10.1038/s41556-026-01887-y
Nat Struct Mol Biol. 2026 Mar 05.

Function and regulation of the mitochondrial stress response.

Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.

As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.

DOI: https://doi.org/10.1038/s41594-026-01769-9
Nat Cardiovasc Res. 2026 Mar 04.

Ventricular assist device unloading reverses microvascular senescence in single ventricle disease.

Xiao Li, Diwakar Turaga, Yi Zhao, Chang-Ru Tsai, Richard Gang Li, Yuka Morikawa, Hanna J Tadros, Md Abdul Hassan Samee, Iki Adachi, James F Martin.

Individuals with hypoplastic left heart syndrome (HLHS) have an underdeveloped left ventricle and require surgery to reconfigure blood flow for survival. Here we profiled the HLHS right-ventricular microenvironment by single-nucleus RNA sequencing and spatial transcriptomics at birth (before heart failure), after surgery with heart failure and after ventricular assist device (VAD) unloading (reduced hypoxia and volume overload). We show that HLHS cardiomyocytes, both within the heart and when derived from induced pluripotent stem cells, are intrinsically senescent. The HLHS myocardium contained a senescent microvascular niche with endothelial cells, pericytes and YAP-high fibroblasts, consistent with hypoxic and mechanical stress. This senescent niche is similar to adult myocardial infarction but not pediatric dilated cardiomyopathy with heart failure, pointing to a prominent role of hypoxia in senescence. The microvascular senescent niche was improved by VAD, providing insight into the potential to reverse cardiac cell states that lead to heart failure.

DOI: https://doi.org/10.1038/s44161-026-00790-x
Nat Commun. 2026 Mar 06.

STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.

Isshin Shiiba, Yuto Ishikawa, Hijiri Oshio, Naoki Ito, Fuya Yamaguchi, Shun Nagashima, Hideya Ando, Keitaro Umezawa, Yuri Miura, Yuhei Araiso, Koki Nakamura, Yusuke Hirabayashi, Ryoko Inatome, Shigeru Yanagi.

Mitochondria form contact sites with multiple organelles to coordinate diverse cellular processes. Melanosomes, lysosome-related organelles, undergo stepwise maturation to synthesize and store melanin, but how they interact with mitochondria remains unclear. Here we show that mitochondria-melanosome contacts dynamically increase during melanosome maturation and are mediated by STIM1-MFN2 interactions. Using a NanoBiT-based reporter system, MiMSBiT (Mitochondria-Melanosome contact reporter applying NanoBiT), to monitor reversible mitochondria-melanosome contacts in living cells, we demonstrate that STIM1 localizes to melanosomes and promotes their contact with mitochondrial MFN2. A transient decrease in melanosomal lumen calcium induces STIM1 clustering and enhances its association with MFN2. These contacts locally increase mitochondrial ATP availability, leading to melanosome lumen acidification via proton channel activation. This acidification facilitates PMEL fibrillation, a key step in melanosome maturation. Together, our findings reveal a mechanism by which mitochondria-melanosome contacts regulate melanosome maturation.

DOI: https://doi.org/10.1038/s41467-026-70282-w
Semin Cell Dev Biol. 2026 Mar 03. pii: S1084-9521(26)00004-2. [Epub ahead of print]179-180 103670

Epithelial cell plasticity in metazoans: Evolutionary insights into roles and mechanisms.

Hiroki Nagai, Yu-Ichiro Nakajima.

  Epithelial tissues function as multicellular communities that preserve tissue integrity while adapting to diverse environmental stresses by altering cell behaviors. A striking manifestation of such adaptability is cell plasticity, the ability of differentiated cells to revert to stem-like states or adopt alternative fates. Once considered rare and confined to highly regenerative species, cell plasticity is now recognized across the metazoan tree. In early-branching animals such as sponges and cnidarians, transdifferentiation and dedifferentiation are integral to life-cycle transitions and regeneration, whereas in more complex organisms, these processes typically emerge under stress, including stem cell loss or environmental perturbations. Here, we examine epithelial cell plasticity through evolutionary, cellular, and molecular perspectives. Focusing on the intestinal epithelium, we explore findings from mammalian and Drosophila models showing that progenitors and even terminally differentiated cells can dedifferentiate in response to external stimuli that disrupt homeostasis, such as pathogen infection and nutrient fluctuations. We further discuss conserved mechanisms involving intercellular signaling (e.g., Notch, EGFR, and JAK-STAT) and chromatin states primed for reprogramming, modulated by metabolic cues. Together, these insights position cell plasticity as an ancient environmental adaptation strategy, shaped by conserved molecular toolkits and refined by species- and cell lineage-specific innovations.

Keywords:  Basal metazoans; Cell plasticity; Environmental responses; Epithelia; Regeneration; Stem cells

DOI:  https://doi.org/10.1016/j.semcdb.2026.103670
Sci Adv. 2026 Mar 06. 12(10): eaeb9507

Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.

Martin C Moncrieffe, Prasanna Suresh, Joe Boyle, Yuhao Cui, Bharti Nawalpuri, Brett Verstak, Yu P Zhang, Ziwei Zhang, Marcus Taylor, Edward H Egelman, Nicholas Gay, David Klenerman, Clare Bryant.

Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown. Here, using cryo-electron microscopy and biophysical characterization of full-length TRIF in vitro, we show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. Endogenous TRIF, however, is predominantly monomeric in the absence of ligand, only forming TRIFosome oligomers in macrophages after stimulation of TLR4 or TLR3 when large, macromolecular signaling complexes form. TRIFosomes are fully formed 45 min after TLR3 or 60 min after TLR4 stimulation, commensurate with activation of nuclear factor κB in these cells. TLR3/4 activation triggers rapid interferon signaling prior to TRIFosome formation through monomeric TRIF, unexpectedly suggesting that a macromolecular platform of TRIF is not required to drive this signaling pathway. Collectively, these data show TRIFosome macromolecular platform formation and, unexpectedly, that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.

DOI: https://doi.org/10.1126/sciadv.aeb9507
Nat Immunol. 2026 Mar 03.

Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.

Zhenrui Li, Beisi Xu, Piyush Sharma, Cliff Guy, Emilio Boada-Romero, Katherine Verbist, Ao Guo, Luigi Mari, Suresh Poudel, Mao Yang, Douglas R Green.

The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active integrin barrier requires the Rubicon-VPS34 complex, which recruits phospholipase D (PLD) to regulate integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.

DOI: https://doi.org/10.1038/s41590-026-02452-3
Nat Cell Biol. 2026 Mar 05.

Acidic niche sugar shield blocks ferroptosis.

Mario Palma, Jessalyn M Ubellacker.

DOI: https://doi.org/10.1038/s41556-026-01899-8
Mol Cell. 2026 Mar 04. pii: S1097-2765(26)00125-5. [Epub ahead of print]

Accessory subunits of PRC2 mimic H3K27me3 to restrict the spread of Polycomb domains.

Samuel C Agius, Marion Boudes, Evan Healy, Yoona Kim, Yi-Cheng Chang, Melanie Murray, Jan Manent, Jeanette Rientjes, Zhihao Lai, Sophie Nixon, Jihane Homman-Ludiye, Vitalina Levina, Edwina McGlinn, Chen Davidovich.

  The Polycomb repressive complex 2 (PRC2) is essential for normal development by maintaining developmental gene repression. PRC2 deposits the repressive chromatin mark H3 lysine 27 tri-methyl (H3K27me3) through a read-write loop that involves direct interactions between PRC2 and H3K27me3. According to current models, the PRC2-H3K27me3 read-write loop is initiated by the PRC2 subunits JARID2 and PALI1 that mimic H3K27me3. However, it is unknown what restricts the PRC2-H3K27me3 read-write loop from spreading H3K27me3 indefinitely. To answer this question, we generated mutant mice where PRC2 subunits cannot mimic H3K27me3. Unexpectedly, the mutations led to delayed Hox gene activation and a homeotic transformation characteristic of a Polycomb gain of function in vivo and the spread of H3K27me3 beyond Polycomb domains in stem cells. Collectively, we show that H3K27me3 mimicry evolved to compete against the PRC2-H3K27me3 read-write loop in a process that restrains PRC2 and restricts the spread of Polycomb domains.

Keywords:  H3K27me3; H3K27me3 mimicry; JARID2; PALI1; PRC2; Polycomb; allostery; epigenetics; facultative heterochromatin; synergy

DOI:  https://doi.org/10.1016/j.molcel.2026.02.011
J Cell Sci. 2026 Feb 15. pii: jcs263423. [Epub ahead of print]139(4):

DNA double-strand break response at a glance.

Francesca Esposito, Sofia Francia.

  DNA double-strand breaks (DSBs) are among the most cytotoxic and most frequent lesions that arise in the mammalian genome; they occur as a result of both external insults and internal metabolic activities. Failures in damage signalling and repair of DSBs can result in permanent cell cycle arrest, cellular senescence, cell death or the accumulation of mutations and genomic instability - events that ultimately disrupt tissue homeostasis. To reduce these detrimental outcomes, cells have evolved a sophisticated and tightly coordinated network of mechanisms for detecting, signalling and repairing DNA lesions, collectively known as the DNA damage response (DDR). Repair occurs within the chromatin landscape, with DDR sensors, mediators, signalling kinases and ubiquitin ligases rapidly recruited to the site of damage. Simultaneously, local chromatin modifications and remodelling take place, which also modulate local transcriptional activity. More complex chromatin dynamics are subsequently orchestrated within the three-dimensional nuclear space - persistent DSBs are actively relocated to specialized nuclear domains and chromatin compartments undergo spatial reorganization to facilitate efficient repair. In this Cell Science at a Glance article and the accompanying poster, we explore the interplay between local and global chromatin dynamics that coordinate DSB repair and preserve genome integrity within the context of a highly dynamic epigenome.

Keywords:  Chromatin; DDR; DNA damage repair pathways; Double strand breaks

DOI:  https://doi.org/10.1242/jcs.263423
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2516372123

Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.

Ethan Levien, Joon Ho Kang, Kuheli Biswas, Scott R Manalis, Ariel Amir, Teemu P Miettinen.

  Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size homeostasis from bacteria to cancer. It remains unclear whether this variability arises from stochasticity in cell growth or division processes, or from cell-size-dependent growth regulation. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along long ancestral lineages. We first show that correlations between growth rates and cell-size nor asymmetric divisions explain cell-to-cell growth variability. We then isolate growth fluctuations by smoothing and detrending the growth rate dynamics using a Gaussian process regression. We find that these growth fluctuations drive cell-to-cell growth variability within ancestral lineages despite being independent of cell divisions, cell cycle, and cell size. Overall, our results provide a quantitative framework for understanding single-cell growth rates, and indicate that cell-intrinsic long-term patterns in growth are a byproduct of short-term growth fluctuations.

Keywords:  cell divisions; cell growth; cell size; cellular noise; heterogeneity

DOI:  https://doi.org/10.1073/pnas.2516372123
Circulation. 2026 Mar 02.

P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes.

Lei Yan, Jialei Zheng, Zhengkai Lu, Anqi Zhu, Min Ye, Jufeng Meng, Juan Tang, Hui Zhang.

   BACKGROUND: Ischemic heart disease remains a leading cause of mortality worldwide, with adverse remodeling after myocardial infarction driven by inflammation and cardiomyocyte loss. Although cytotoxic lymphocytes exacerbate myocardial injury and P16 marks cellular senescence in diseased hearts, the cell type-specific functions of P16+ populations remain unclear.
METHODS: Using p16-CreER;R26-tdT reporter mice, we mapped P16+ cell heterogeneity after myocardial infarction. Senolytic effects were assessed with combined dasatinib and quercetin treatment. Transcriptomic profiling (bulk and single-cell RNA sequencing) of sorted P16+ cells identified secreted factors, validated through in silico predictions and quantitative polymerase chain reaction. Intercellular communication was analyzed using CellChat. Functional relevance was tested through CCL8 (cytokine [C-C motif] ligand 8) neutralization, Ccl8 deletion in P16+ cells, lymphocyte depletion, and intersectional genetic ablation of P16+ fibroblasts or macrophages using dual-recombinase systems (p16-DreER;Pdgfra-CreER;R26-lr-tdT-DTR and p16-DreER;Cx3cr1-CreER;R26-lr-tdT-DTR).
RESULTS: P16 was induced in fibroblasts, macrophages, coronary endothelial cells, and cardiomyocytes after myocardial infarction. Dasatinib and quercetin treatment selectively eliminated P16+ macrophages and fibroblasts, improving cardiac function. Transcriptomic analysis identified P16+ fibroblasts and macrophages as the main sources of CCL8. CCL8 blockade reduced infiltration of cytotoxic lymphocytes (CD8+ T cells and natural killer cells), decreased cardiomyocyte apoptosis, and enhanced repair. Genetic deletion of Ccl8 in P16+ cells reproduced these benefits. It is important to note that ablation of P16+ fibroblasts, but not macrophages, diminished fibrosis and improved function, and depletion of CD8+ T cell attenuated adverse remodeling.
CONCLUSIONS: P16+ cells orchestrate maladaptive remodeling after myocardial infarction through CCL8-dependent recruitment of cytotoxic lymphocytes, particularly CD8+ T cells, which drive cardiomyocyte apoptosis. Targeting P16+ fibroblasts or blocking CCL8 offers a promising therapeutic approach for ischemic heart disease.

Keywords:  CCL8; P16; cytotoxic lymphocytes; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077172
Nat Commun. 2026 Mar 03.

Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.

Lathan Lucas, Phoebe S Tsoi, My Diem Quan, Kyoung-Jae Choi, Josephine C Ferreon, Allan Chris M Ferreon.

Proteins undergo phase separation to form membraneless condensates that spatially organize biomolecular interactions. These condensates can support cellular physiology or instigate pathological protein aggregation. Tau and α-synuclein (αSyn) are neuronal proteins that form heterotypic Tau:αSyn condensates associated with physiological and pathological processes. Tau and αSyn regulate microtubules, but also misfold and co-deposit in aggregates linked to neurodegenerative disease, highlighting the ambivalent impact of Tau:αSyn condensation in health and disease. Here, we show that Tubulin modulates Tau:αSyn condensates by promoting microtubule interactions and inhibiting homotypic and heterotypic pathological oligomers. In the absence of Tubulin, Tau-driven condensation accelerates formation of pathogenic Tau:αSyn heterodimers and amyloid fibrils. Tubulin partitioning into condensates promotes microtubule polymerization and prevents Tau and αSyn oligomerization. We identify distinct Tau and αSyn structural states in pathological Tubulin-absent versus physiological Tubulin-rich condensates. In neuronal models, microtubule loss drives pathological oligomer formation and neurite loss, whereas inducible Tau condensation stabilizes microtubules.

DOI: https://doi.org/10.1038/s41467-026-69618-3
Nat Struct Mol Biol. 2026 Mar 06.

A proteome-wide dependency map of protein interaction motifs.

Sara M Ambjørn, Bob Meeusen, Johanna Kliche, Juanjuan Wang, Dimitriya H Garvanska, Thomas Kruse, Blanca Lopez Mendez, Matthias Mann, Niels Mailand, Emil P T Hertz, Norman E Davey, Jakob Nilsson.

Short linear motifs (SLiMs) are the most ubiquitous protein interaction motifs within unstructured regions of the human proteome, yet their contribution to cellular homeostasis remains poorly understood. Here, to systematically assess SLiM function, we applied base editing to mutate all reported and a set of computationally predicted SLiMs defined by SLiM-like evolutionary patterns. By screening 7,293 SLiM-containing regions with 80,473 mutations in HAP1 cells, we define a SLiM dependency map identifying 450 reported and 264 predicted SLiMs required for normal cell proliferation. Mutational consequences were highly reproducible in RPE1 cells, with differences attributed to cell-line-specific gene essentiality. We show that many predicted SLiMs affecting proliferation do not belong to existing classes and identify binding partners for several of these, providing mechanistic insight into a disease-associated ANKRD17 mutation. Our study provides a proteome-wide resource on SLiM essentiality uncovering numerous uncharacterized essential SLiMs.

DOI: https://doi.org/10.1038/s41594-026-01762-2
Nat Cell Biol. 2026 Mar 06.

Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.

Alexis Betrancourt, M Talha Cinko, Ana Beatriz Varanda, Maykel Arias, Iratxe Uranga-Murillo, Natacha Peña, Lucia-Maria Kaps, Long Fung Chau, Bianca Buratti, Johannes Brägelmann, Diego de Miguel, Kerstin Becker, Ramona Casper, Rocio Martin, Antonio Alcami, Brian J Ferguson, Julian Pardo, Eva Rieser, Henning Walczak.

Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.

DOI: https://doi.org/10.1038/s41556-026-01886-z
Cell. 2026 Mar 04. pii: S0092-8674(26)00162-5. [Epub ahead of print]

Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs.

Fei Teng, Jing Liu, Tongtong Cui, Xiangtian Tan, Kailun Liu, Zongren Hou, Li Zhou, Yuanzhi Xie, Rongqi Li, Da Li, Bojin Li, Dongmei Wang, Qi Zhou, Baoyang Hu, Wei Li.

  Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effectively facilitate targeted degradation of extracellular proteins and enable transcytosis across the blood-brain barrier. In vivo administration of SPYTACs effectively reduces peripheral and cerebral Aβ burden, attenuates synapse loss, and improves cognitive function in 5×FAD mice at both prodromal and symptomatic stages. Notably, SPYTAC treatment shows fewer side effects, including intracerebral hemorrhage and inflammation, compared with conventional immunotherapies. The high modularity and genetic encodability enable SPYTACs to target customized disease-causing proteins, underscoring their therapeutic versatility and translational promise across diverse diseases driven by pathogenic proteins.

Keywords:  AD; Alzheimer’s disease; Aβ; SPYTAC; amyloid-β; eTPD; extracellular targeted protein degradation

DOI:  https://doi.org/10.1016/j.cell.2026.01.034
Mol Cell. 2026 Mar 03. pii: S1097-2765(26)00102-4. [Epub ahead of print]

Global profiling of nascent chain interactors reveals TRIM25 as a co-translational E3 ubiquitin ligase.

Wenfeng Xiong, Zheng Ser, Radoslaw Mikolaj Sobota, Zhewang Lin.

  Nascent polypeptide chains emerging from the ribosome engage a range of co-translational factors at distinct phases of translation. These co-translational interactions are crucial for proper protein biogenesis and quality control pathways to maintain protein homeostasis. Hence, the systematic identification of these co-translational interactors provides insights into how distinct polypeptide fates are determined. Here, we developed nascent-chain interactor profiling (NCIP), a metabolic-labeling- and chemical-crosslinking-enabled proteomics method to identify proteins interacting with nascent polypeptide chains at a proteome-wide scale. Results from NCIP support the co-translational assembly model of multiple protein complexes and reveal TRIM25 as a co-translational E3 ubiquitin ligase. TRIM25 ubiquitinates misfolded nascent chains for quality control at the ribosome. Our results provide a generalizable framework to systematically profile co-translational interactors.

Keywords:  co-translational E3 ubiquitin ligase; nascent chain interactors; protein quality control

DOI:  https://doi.org/10.1016/j.molcel.2026.02.007
Sci Adv. 2026 Mar 06. 12(10): eaed3579

Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.

Kenneth Ehses, Jorge P López-Alonso, Odetta Antico, Yannik Lang, Till Rudack, Abdussalam Azem, Miratul M K Muqit, Iban Ubarretxena-Belandia, Rubén Fernández-Busnadiego.

Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo-electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo-electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.

DOI: https://doi.org/10.1126/sciadv.aed3579
NPJ Regen Med. 2026 Mar 05.

Single-cell chromatin accessibility landscape of cardiac non-myocytes identifies tissue repair program during heart regeneration.

Zihao Chen, Yage Nie, Liying Huang, Ni Zeng, Jixing Gong, Yichen Gao, Qiye Wen, Xiaoyong Chen, Xiaoqian Ji, Yun Li, Tian Lan, Lan Jiang, Jia Wang, Jin Xu, Nan Cao.

The restricted regenerative potential of adult hearts poses a significant barrier to effective repair following injury. In contrast to numerous vertebrates, mammalian hearts exhibit only transient neonatal renewal capacity during the initial days of life. Beyond cardiomyocytes, understanding the diverse compositions of non-cardiomyocytes (non-CMs) is imperative for maintaining heart microenvironment homeostasis during neonatal heart regeneration. Here, we conduct single-cell ATAC sequencing on neonatal hearts at varying time points post-apical resection to profile the epigenetic landscape. Intriguingly, fibroblasts and endothelial cells, as the most abundant populations in the heart, exhibit the most dynamic chromatin remodeling upon injury. Furthermore, we reveal CEBPD and AP-1 family transcriptional factors as pivotal trans-regulators orchestrating these alterations, governing beneficial fibroblast activation and endothelial cell angiogenesis crucial for cardiac regeneration, respectively. Collectively, our study delineates the cellular identity of non-CMs at the epigenome level using single-cell approaches, offering insights into cell type-targeted interventions for heart regeneration.

DOI: https://doi.org/10.1038/s41536-026-00465-y
Nat Commun. 2026 Mar 06.

The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.

Qixia Xu, Gaoxiang Li, Hongwei Zhang, Zhirui Jiang, Xiuxia Gao, Zi Li, Larissa G P Langhi Prata, James L Kirkland, Guilong Zhang, Yu Sun.

Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics suggests that dihydromyricetin promotes nuclear translocation of peroxiredoxin 2 (PRDX2) to facilitate DNA repair in senescent cells. In prematurely aged mice, dihydromyricetin administration mitigates tissue aging and age-related physiological decline. In anticancer regimens, dihydromyricetin improves outcomes of chemotherapy. However, dihydromyricetin demonstrates senolytic activity against senescent microglial cells, whose basal PRDX2 expression remains low, by impairing mitochondrial function to promote apoptosis. In mice developing Alzheimer's disease, dihydromyricetin eliminates senescent microglial cells from amyloid β-protein plaques and alleviates neurodegenerative symptoms. Together, our study proposes dihydromyricetin as a natural senotherapeutic agent for mitigating age-related morbidities, including but not limited to cancers and Alzheimer's disease.

DOI: https://doi.org/10.1038/s41467-026-70302-9
Nat Metab. 2026 Mar 03.

Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.

Yuan Gui, Wenxue Li, Jia-Jun Liu, Yuanyuan Wang, Cameron Jones, Riddhi Bansal, Samantha Mae Mallari, Henry Wells Shaffer, Yanbao Yu, Haiyan Fu, Tracy T Tang, Silvia Liu, Yansheng Liu, Dong Zhou.

The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP-TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.

DOI: https://doi.org/10.1038/s42255-026-01458-3
Sci Signal. 2026 Mar 03. 19(927): eadz6443

Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.

Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah.

The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

DOI: https://doi.org/10.1126/scisignal.adz6443
Mol Cell. 2026 Mar 04. pii: S1097-2765(26)00104-8. [Epub ahead of print]

Self-clustering of three CBX2 molecules drives PRC2 to promote facultative heterochromatinization of Polycomb target genes.

Steven Ingersoll, Abby Trouth, J Carlos Angel, Xinlong Luo, Axel Espinoza, Joey Wen, Chengjie Zhu, Joseph Tucker, Kalkidan Astatike, Christopher J Phiel, Hatim Sabaawy, Tatiana G Kutateladze, Tao P Wu, Tingting Yao, Chao Lu, Srinivas Ramachandran, Xiaojun Ren.

  Phase separation is increasingly recognized in facultative heterochromatinization of Polycomb target genes; however, the mechanisms underlying this process remain obscure. Using single-molecule imaging and tracking, we show that individual condensates in mouse embryonic stem cells (mESCs) contain approximately 3 CBX2 molecules and numerous Polycomb repressive complex (PRC)1 and PRC2 subunits and indicate that the composition and dynamics of condensates are developmentally regulated. We reveal that CBX2 clusters PRC2 and controls the spatial distribution of both PRC2 and H3K27me3. Using genomic approaches, we demonstrate that CBX2 binds to condensate initiation sites, which are enriched for PRC2 nucleation sites. CBX2 deletion causes PRC2 and H3K27me3 to redistribute from their regular targets. By developing a separation-of-function variant, we determine that CBX2 relies on its self-clustering ability to function. These findings collectively support a phase-separation model driven by nucleation and bridging, in which low-abundance proteins self-cluster to initiate condensate assembly, a process tightly coupled to function.

Keywords:  CBX2; H3K27me3; PcG; Polycomb; bridging-induced phase separation; chromatin; nucleation; phase separation; polymer-polymer phase separation; single-molecule imaging

DOI:  https://doi.org/10.1016/j.molcel.2026.02.009
Nat Aging. 2026 Mar 03.

Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.

Emma K Costa, Jingxun Chen, Ian H Guldner, Lajoyce Mboning, Natalie Schmahl, Aleksandra Tsenter, Rahul Nagvekar, Man-Ru Wu, Patricia Moran-Losada, Louis-S Bouchard, Sui Wang, Param Priya Singh, Matteo Pellegrini, Anne Brunet, Tony Wyss-Coray.

Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA sequencing on 13 tissues at six different ages in male and female African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset revealed varying strength of sex-age interactions across killifish tissues and age-altered genes and biological pathways that are evolutionarily conserved in mice and humans. We discovered a female-biased myeloid shift with age in the killifish hematopoietic organ, developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We showed the importance of sex-specific clocks for selected tissues, validated the tissue clocks with an independent transcriptomic dataset and used them to evaluate different lifespan interventions in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

DOI: https://doi.org/10.1038/s43587-026-01074-6
Nature. 2026 Mar 03.

Genetically encoded assembly recorder temporally resolves cellular history.

Yuqing Yan, Jiaxi Lu, Zhe Li, Zuohan Zhao, Timothy F Shay, Shunzhi Wang, Yaping Lei, Yimei Wang, Wei Chen, Patrick Parker, Hongru Yang, Aileen Qi, Yongzhi Sun, Dwight E Bergles, David Baker, Dingchang Lin.

Cells constantly change their molecular state in response to internal and external cues1. Mapping cellular activity in tissues with spatiotemporal precision is essential for understanding organ physiology, pathology, and regenerative processes. Current cell-sensing modalities primarily rely on either endpoint analysis that takes static snapshots, or real-time sensing that monitors a small subset of cells3,4. Here, we introduce Granularly Expanding Memory for Intracellular Narrative Integration (GEMINI), an in cellulo recording platform that leverages a computationally designed protein assembly as an intracellular memory device to record the history of individual cells. GEMINI grows predictably within live cells, capturing cellular events as tree-ring-like fluorescent patterns for imaging-based retrospective readout. Absolute chronological information of activity histories is attainable with hour-level accuracy. GEMINI effectively maps differential NFκB-mediated transcriptional changes, resolving fast dynamics of 15 minutes and providing quantifiable signal amplitudes. In a xenograft model, GEMINI records inflammation-induced signaling dynamics across tissue, revealing spatial heterogeneity linked to vascular density. When expressed in the mouse brain, GEMINI minimally impacts neuronal functions and can resolve both transcriptional changes and activity patterns of neurons. Together, GEMINI provides a robust and generalizable means for spatiotemporal mapping of cell dynamics underlying physiological and pathological processes in both culture and intact tissues.

DOI: https://doi.org/10.1038/s41586-026-10323-y
Nature. 2026 Mar 04.

Cell-free chromatin state tracing reveals disease origin and therapy responses.

Xubin Chen, Xiaoxuan Meng, Weilong Zhang, Xiawei Zhang, Yaping Zhang, Ping Yang, Yan Liu, Fang Bao, Sen Li, Jing Wang, Changjian Yan, Chunyuan Li, Lingke Zhang, Xiaoyu Hao, Jia Liu, Jing Sun, Zhengting Wang, Yu Tian, Liqing Zhu, Yan Hou, Zongchao Liu, Wenqing Li, Lan Mi, Xinyu Qi, Yanzhu Yue, Peng Du, Guoqiang Chen, Junke Zheng, Liping Dou, Hongmei Jing, Aibin He.

Cell-free DNA in blood originates from fragmented chromatin released by dying cells from both healthy and diseased tissues1,2. These fragments carry rich molecular modalities that can reveal pathological alterations in tissues of origin3-10. Here we develop cf-EpiTracing, a highly sensitive automated platform that profiles histone modifications in cell-free DNA from as little as 50 μl of human plasma. By integrating multimodal chromatin states with machine learning, cf-EpiTracing enables accurate deconvolution of cell types of origin. We generated 2,417 cf-EpiTracing profiles from plasma of 125 healthy individuals and 549 patients with inflammatory bowel disease, colorectal cancer, coronary heart disease or lymphoma. cf-EpiTracing enabled unbiased identification of primary diseased tissues and other organ involvement, stratification of B cell lymphoma subtypes with different genetic and epigenetic underpinnings, and detection of early-stage diseases or lesions. Surveying dynamics of epigenetic signatures uncovered disease transformation from follicular lymphoma to diffuse large B cell lymphoma. Further, cf-EpiTracing revealed genomic translocations and epigenetic alterations in patients with mantle cell lymphoma. Of note, our study leverages holistic epigenetic signatures, independently of knowledge of gene transcription, to accurately report recurrence risk and therapeutic response. Together, these findings establish cf-EpiTracing as an automated, non-invasive, epigenome-centric framework with broad applications in early diagnosis, molecular subtyping and prognostic prediction.

DOI: https://doi.org/10.1038/s41586-026-10224-0
Nat Aging. 2026 Mar 06.

The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.

Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.

DOI: https://doi.org/10.1038/s43587-026-01087-1
Sci Adv. 2026 Mar 06. 12(10): eaeb1271

Compressive stress-driven Piezo1 activation and Rho-ROCK mechanotransduction promote tumor progression via epigenetic mechanical memory.

Sarah T Boyle, David Gallego-Ortega, Edward J Buckley, Emmanuelle Cognard, M Zahied Johan, Zahra Esmaeili, Makoto Kamei, Kate Poole, Michael S Samuel.

Rapidly growing tumors experience high tissue-level forces, particularly when growing within a restricted space. These require counteracting by intracellular forces to prevent tissue damage. Here, we reveal the ion channel Piezo1 as a mechanosensor of compressive force, activating Rho-Rho kinase (ROCK) mechanotransduction to generate intracellular forces and enhancing malignant characteristics of tumors. Compressive stress promoted cancer growth in vivo in a Rho-ROCK-dependent manner. Silencing Piezo1 abolished compression-induced Rho-ROCK activation and tumor progression in this model. Accordingly, elevated PIEZO1 is associated with 35% poorer survival of patients with breast cancer. We show that acute compressive forces engender epigenetic mechanical memory via Piezo1-activated Rho-ROCK signaling, promoting tumor growth in vivo. Compressive stress promoted ROCK-dependent histone modifications associated with open chromatin, including acetylation of key histone 3-lysine residues, regulating the expression of cancer-related genes across cell, explant, and in vivo tumor models. Our observations suggest that the PIEZO1-RHO-ROCK axis links tissue-level forces to persistent tumor-promoting epigenetic changes and merits evaluation as a mechanotherapy target in cancer.

DOI: https://doi.org/10.1126/sciadv.aeb1271
Nat Cardiovasc Res. 2026 Mar 03.

Attenuation of epicardial activation and myofibroblast abundance via the Fbln2-Nupr1b axis stimulates cardiac regeneration in zebrafish.

Gülsüm Kayman Kürekçi, Gursimran Kaur Bajwa, Shaoqiu Zhang, Séverine Leclerc, Emilie de Chantal, Darrell Belke, Gregor Andelfinger, Justin F Deniset, Rubén Marín-Juez.

After injury, the adult human heart fails to regenerate and forms a persistent fibrotic scar. By contrast, fibrosis is transient in the injured zebrafish heart, facilitating cell recruitment and providing regenerative cues. The mechanisms that restrain excessive fibrosis while enabling regeneration remain poorly understood. Here we show that fibulin-2 (Fbln2) regulates specific populations of activated epicardial cells to balance the response to cardiac injury. Using genetic tools for Fbln2 dosage, we find that attenuation of epicardial activation stimulates regenerative programs. Mechanistically, we identify epicardial nuclear protein 1b (Nupr1b) as an Fbln2 effector. Using gain- and loss-of-function approaches, we show that Nupr1b controls epicardial myofibroblast abundance. Notably, epicardial-specific overexpression of nupr1b rescued fbln2 mutant phenotypes. These findings shed light on how modulation of epicardial cell state transitions through Fbln2-Nupr1b signaling regulates regenerative responses after cardiac injury.

DOI: https://doi.org/10.1038/s44161-026-00785-8
Nature. 2026 Mar 02.

BCDX2-CX3 and DX2-CX3 complexes assemble and stabilize RAD51 filaments.

Christopher W Koo, Jiaqi Xiao, Sebastien Coassolo, Jie Liu, Christine Yu, Caleigh Azumaya, Steven K Gore, Tommy K Cheung, Bobby Brillantes, Chris M Rose, Wolf-Dietrich Heyer, Claudio Ciferri, Stanislau Yatskevich.

The repair of DNA double-strand breaks by homologous recombination (HR) is essential for genomic integrity, and its dysregulation is a hallmark of cancer1. Central to HR is the RAD51 recombinase, whose assembly into a nucleoprotein filament is governed by five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3)2. Mutations in any of these proteins predispose individuals to multiple cancers or genetic disorders3-6. These paralogs are thought to form two functionally separate complexes, BCDX2 (RAD51B-C-D-XRCC2) and CX3 (RAD51C-XRCC3), that act independently at different stages of HR7-11. Here, we demonstrate that all five paralogs can assemble into a single, ATP-dependent BCDX2-CX3-RAD51 supercomplex. The architecture of this assembly bound to single-stranded DNA (ssDNA) reveals a contiguous filament where the CX3 module stacks atop BCDX2, creating a protofilament template for RAD51 filament formation. We further identify a novel, RAD51B-independent DX2-CX3 complex (RAD51D-XRCC2-RAD51C-XRCC3) functioning as a stable RAD51 anchor on ssDNA, and we capture it in multiple states, including capping RAD51 filament segment. These distinct assemblies are differentially regulated by ATPase activity, defining a dynamic BCDX2-CX3 "loader" and a stable DX2-CX3 "anchor" that provide functional modularity to the HR machinery. This work provides a unifying mechanism for human RAD51 paralog function and delivers an atomic blueprint for interpreting disease-causing mutations.

DOI: https://doi.org/10.1038/s41586-026-10314-z
Mol Cell Biol. 2026 Mar 02. 1-19

Loss of Splicing Homeostasis as a Hallmark of Aging.

Stefano Donega, Myriam Gorospe, Lorna W Harries, Luigi Ferrucci.

  Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.

Keywords:  Splicing; adaptive gene expression programs; aging; proteomic diversity; senescence

DOI:  https://doi.org/10.1080/10985549.2026.2627235
Nat Commun. 2026 Mar 03.

GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.

Yu Shi, Kai Yan Cheng, Thi Tun Thi, Yifan Wang, Yang Yang, Xiaoyun Cao, Vanna Chhay, Yujia Shen, Yuchen He, Tianyun Zhao, Yan Ting Lim, Amy Deik, Courtney Dennis, Kerry Pierce, Kevin Bullock, Martin Wabitsch, Clary B Clish, Alexander S Banks, Radoslaw M Sobota, Chad A Cowan, Haojie Yu.

The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. In mice, both constitutive and acute GPR146 depletion protect against diet-induced obesity and hepatic steatosis. Notably, adipose-specific, but not liver-specific, GPR146 deletion reduces hepatic lipid accumulation by limiting free fatty acid (FFA) influx. Mechanistically, GPR146 promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating FFA. Together, these coordinated actions increase FFA delivery to the liver, promoting triglyceride accumulation. Our findings establish GPR146 as a pleiotropic regulator of adipose tissue biology and a potential therapeutic target for MASLD.

DOI: https://doi.org/10.1038/s41467-026-70136-5
Dev Cell. 2026 Mar 02. pii: S1534-5807(26)00043-2. [Epub ahead of print]

Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation.

Zhen Zhang, Ben Jin, Chenyu You, Ya Li, Li Lin, Jianlong Sun.

  Myeloablative chemotherapy induces hematopoietic regeneration, a process orchestrated by hematopoietic stem cells (HSCs). Although prior studies have documented enhanced HSC differentiation during this process, the temporal changes in HSC fate in response to such stress remain unclear. Here, we employed lineage tracing and mathematical modeling to investigate the cell-fate dynamics of Endothelial Protein C Receptor (EPCR)-high HSCs following 5-fluorouracil (5-FU)-induced myeloablation. Our analysis revealed a transient surge in HSC differentiation immediately after 5-FU treatment, generating primarily myeloid-biased multipotent progenitors (MPPs)-subsets that typically receive limited HSC input under steady-state conditions. Following this initial cell-fate switch, elevated HSC differentiation persisted but rapidly reverted to the homeostatic differentiation pattern observed in unperturbed hematopoiesis. Additionally, our data highlight a substantial contribution of MPPs to myeloid and lymphoid lineage regeneration following 5-FU challenge. Together, these findings delineate the sequential fate transitions adopted by HSCs during severe myeloablation and identify stage-specific differentiation patterns of HSCs in stress hematopoiesis.

Keywords:  5-fluorouracil; hematopoietic stem cell; lineage tracing; stress hematopoiesis

DOI:  https://doi.org/10.1016/j.devcel.2026.02.003
Nat Immunol. 2026 Mar;27(3): 543-555

Piezo1-dependent activation of stromal cells ignites muscle inflammation in exercise and injury and is associated with inflammaging.

P Kent Langston, Jayashree Vijaya Raghavan, Christophe Benoist, Diane Mathis.

As the actuator of movement and a key regulator of organismal metabolism, skeletal muscle is a site at which inflammatory responses must be carefully calibrated to counteract stressors while preventing protracted functional impairments. Exercise, injury and aging are common forms of stress associated with inflammation; yet the specific inducers and sensors driving such inflammation remain poorly characterized. Multipronged assessment of acute and chronic endurance exercise models uncovered a role for muscle mesenchymal stromal cells in transducing exercise-induced mechanical stress into local inflammatory responses and that the mechanosensitive ion channel Piezo1 is the primary molecular sensor. Mechanosensing by stromal cells is also necessary for appropriately timed inflammatory and myogenic responses to acute muscle injury and is associated with age-related muscle inflammation. These findings highlight sensing of altered tissue stiffness by Piezo1 on muscle mesenchymal stromal cells as a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.

DOI: https://doi.org/10.1038/s41590-026-02435-4
Cancer Res. 2026 Mar 05.

Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium.

Oscar Pellon-Cardenas, Prateeksha Rout, Sohaib Hassan, Emily Fokas, Isha Patel, Jay Patel, Xia Qiu, Ping He, Olivia Nussbaum, Alex Wu, Rohit Kumar, Masuda Akther, Alexandra Logerfo, Siwen Wu, Daniel Wagner, Dario Boffelli, Katherine D Walton, Kevin Tong, Jahangir Iqbal, Ruoxuan Xiao, Lei Chen, Jason R Spence, Nicholas J Bessman, Elisa Manieri, Ramesh A Shivdasani, Michael P Verzi.

Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt-villus axis in the intestine and provide a niche that supports intestinal stem cells. Here, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations revealed a dynamic reprogramming of PDGFRA+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0101
FEBS J. 2026 Mar 03.

Aurora B kinase phosphorylates keratin 8 at the cleavage furrow to drive spatially restricted intermediate filament disassembly during cytokinesis.

Valentina Rossio, Joao A Paulo.

  Keratins form intermediate filament networks that stabilize epithelial cells and many cancer cells. During cytokinesis, these filaments must be locally disassembled at the cleavage furrow to allow furrow ingression and cell separation. In this issue, Harmanda et al. demonstrate that Aurora B kinase directly phosphorylates Keratin 8 at multiple sites, with pS34-K8 being highly enriched specifically at the contractile ring and the midzone. Using in vitro kinase assays, mass spectrometry, phospho-specific antibodies, CRISPR Keratin 8 knockout, and non-phosphorylatable/phosphomimetic mutants, the authors show that Aurora B-mediated phosphorylation promotes keratin filaments disassembly at the furrow. Noticeably, Keratin 8 scaffolds Aurora B to the midzone, creating a positive feedback loop that is essential for cytokinesis in epithelial cancer cells. These data reveal a novel, spatially regulated mechanism linking Aurora B to intermediate filament dynamics and highlight potential therapeutic opportunities in carcinomas that overexpress Keratin 8.

Keywords:  Aurora B; Keratin; cytokinesis; phosphorylation; spatial regulation

DOI:  https://doi.org/10.1111/febs.70469
Eur Heart J. 2026 Mar 06. pii: ehag095. [Epub ahead of print]

Senescence-related myocardial dysfunction: keeping a young heart.

Ramzi A Ajjan, Robert T R Huckstepp, Naveed Akbar, Johann Bauersachs, Jesher Ching Wai Lok, Juel Choppy-Madeleine, Gary Christopher, Mayank Dalakoti, Emily Dawson-Plincke, John Dodds, Georgina M Ellison-Hughes, Costanza Emanueli, Christopher H George, Anushka Goyal, Victoria Higginbotham, Lorenz Holzner, Venkateswarlu Kanamarlapudi, Paolo Madeddu, Claudio Mauro, Fiona Lewis-McDougall, Andrew J Murray, Renita Peter Damien Genetus, Emma Short, Mark A Sussman, Adriana A S Tavares, Samuel Thompson, Morya Wadodkar, Stuart R G Calimport, Barry L Bentley.

The heart, a vital organ, works without interruption and constantly adjusts to the ever-changing demands on our body. It adapts to physiological and pathological changes, including exercise and emotional state, as well as metabolic, respiratory, and vascular abnormalities. The pumping action of the heart is determined by the health of the myocardium, which undergoes changes with ageing that are both under-investigated and incompletely understood, potentially impacting our approach to pathological conditions. Here, the alterations in cellular, tissue, and gross physiological function of the heart with age are discussed. At the molecular level, non-coding RNAs influence cellular senescence, and extracellular vesicles induce fibrosis through matrix remodelling. Mitochondrial dysfunction and altered fatty acid oxidation reduce cellular energetics, whilst accumulation of reactive oxygen species and steatosis, as well as telomere shortening coupled with reduced autophagy, limit the myocardium's regenerative capability. Loss of cardiomyocytes, combined with senescence, requires compensatory hypertrophy, inducing myocardial stiffness and altered muscle function. In addition to these direct alterations in myocardial characteristics with ageing, other factors that can affect the myocardium indirectly are addressed, including valve calcification, resulting in regurgitation and/or stenosis; vascular abnormalities, reducing compliance and exacerbating hypertension; fibrosis leading to cardiac arrhythmias; and autonomic dysregulation, reducing cardiac adaptability. Finally, potential modulation of cardiac ageing is discussed whilst also addressing which senescent modifications should be considered as ageing-related physiological changes of the myocardium. A better understanding of myocardial ageing will differentiate physiological changes from early, preventable, and reversible pathological changes, consequently helping to optimize management of individuals with or at risk of myocardial disease by taking into account diverse trajectories of myocardial ageing.

DOI: https://doi.org/10.1093/eurheartj/ehag095