Volume 27 Issue 10, October 2025

During wound healing, epithelial gaps trigger curvature-dependent ER remodelling. Tubules form at convex cell edges and promote lamellipodial crawling, whereas ER sheets at concave edges support purse-string contractions. Cytoskeletal forces drive this reorganization and position the ER as a key mechanotransducer in tissue repair.

The transition of a pluripotent stem cell into a differentiated lineage is one of the most complex yet precisely orchestrated events in developmental biology. A study now reveals that mechanical and osmotic forces, long considered background players in guiding this transition, are essential regulators of chromatin accessibility and cell fate decisions.

ATM inhibitors (ATMi) cause cell death by enabling CtIP to induce excessive DNA resection. A study now shows that ERCC6L2 regulates resection by forming condensates with CtIP to prevent its degradation. Loss of ERCC6L2 decreases sensitivity to ATMi, which suggests that ERCC6L2 deficiency can be a biomarker for ATMi resistance.

The AMP-dependent protein kinase AMPK is thought to be activated only when cellular energy levels are low. However, a study now finds that intracellular AMP is generated from extracellular adenosine in an intricate growth signalling cascade, explaining how AMPK can be regulated by extracellular cues.

Glioblastoma (GBM) heterogeneity might arise because of the activation of various gene core regulatory circuitries (CRCs). A new study highlights the central role of HOXB3 in GBM CRCs and how peptide-mediated perturbation of HOXB3-related CRCs in GBM holds potential as treatment for a subset of patients.

The regulatory mechanisms that drive oncogene expression in gliomas remain poorly understood. A study now identifies a role for widespread rearrangements of the enhancer connectome. Such rearrangements are linked to known genetic risk variants, revealing how genetic predisposition contributes to malignancy.

Ageing and cancer are often seen as divergent tissue fates. In our study, we identify a protective programme, called senescence-coupled differentiation (or seno-differentiation), that eliminates cancer-prone stem cells by pushing them to differentiate. Whether melanocyte stem cells follow this path or bypass it under carcinogenic stress determines tissue outcomes: hair greying or melanoma development.

We present CellNavi, a deep learning framework that predicts driver genes that orchestrate cellular transitions by modelling cell states on a biologically meaningful manifold. We demonstrated how CellNavi predictions of driver genes have potential applications in advancing cell therapy, uncovering key factors that drive cellular diseases, and identifying crucial genes involved in drug responses.

This Review discusses the effects of three age-associated stressors—loss of proteostasis, oxidative damage and dysregulated nutrient sensing—on global protein synthesis and highlights how altered translation is used by the cell as a stress sensor.

In this Review, Lusk et al. discuss emerging insights into nuclear pore complex variability with regard to composition and dilation state, and propose nuclear mechanics as a key determinant of driving such plasticity and any associated diseases.

Gasnier et al. identify NOX1 and NPY1R as markers of colon stem cells within the mouse caecum and the middle and distal colorectum, respectively. These stem cells contribute to the initiation of invasive colon tumours in mice.

Mohri et al. show that, in response to genotoxic stress, melanocyte stem cells undergo senescence-associated differentiation, causing their depletion and protecting them against melanomagenesis. This process is suppressed by carcinogens.

Rawal et al. combine intracellular cartography and biophysical modelling to reveal how edge curvature governs endoplasmic reticulum (ER) morphology, showing that curvature-dependent ER reorganization directs distinct modes of epithelial cell migration.

Here the authors show that LC3-associated phagocytosis is initiated by various receptors, which enrich phosphatidylserine in the membrane domains proximal to the phagosome, recruiting Rubicon to the membrane for phagosome maturation.

Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.

Nguyen, Collier et al. find a mitochondria–lysosome inflammatory pathway regulated by the SUMO E3 ligase MAPL, which promotes vesicular mtDNA transport to lysosomes and subsequent gasdermin-dependent lysosomal permeabilization to activate pyroptosis.

Vanni et al. show a role for microtubules in YAP/TAZ mechanosignalling. Mechanoresponsive microtubule reorganization into centrosomal arrays allows for AMOT delivery to pericentrosomal proteasomes and degradation, leading to YAP/TAZ activation.

The authors show that the endoplasmic reticulum-phagy receptor FAM134B interacts with SCAP to regulate cholesterol biosynthesis, sequestering SCAP when endoplasmic reticulum cholesterol is high but dissociating upon low cholesterol levels, allowing SCAP to activate cholesterol synthesis.

McCreery, Stubb et al. show that mechano-osmotic changes in the nucleus induce general transcriptional repression and prime chromatin for cell fate transitions by relieving repression of specific differentiation genes.

Yin, Lin, Cai, Nie and colleagues report phase separation of ERCC6L2 as a mechanism that regulates RNF138-mediated ubiquitination and degradation of CtIP, thereby modulating DNA end resection and treatment response to ATM inhibitors in cancer.

Sun et al. identify a subset of transposable elements that serve as mechano-response enhancer elements that control gene expression and human stem cell fate.

Li, He, Liu and colleagues characterize the dynamic bivalent chromatin landscape during mouse peri-implantation development. They find that factor ZBTB17 works with KDM6A/B to resolve transiently maintained bivalent domains and prime gene activation.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Zhang et al. demonstrate that AMPK can be activated by signalling metabolite, adenosine, under non-stress conditions during Drosophila development. The intestine regulates adenosine levels, thus, remotely controlling wing disc AMPK activation and growth.

Bi, Mo, Liu et al. carry out high-throughput screening and analysis to profile genome-wide pro-tumour enhancers and uncover enhancer connectomes in glioma. In particular, they identify specific single-nucleotide polymorphisms associated with glioma risk and progression.

Zhang et al. delineate the heterogeneity of core regulatory circuitry in glioblastoma and identify HOXB3 condensation as a vulnerability that may be targeted with a therapeutic peptide in mouse models.

The authors integrate single-cell transcriptomic data with prior gene graphs to produce a biologically meaningful cell state manifold that can predict driver genes for genetic perturbations and differentiation events across diverse cell types.