Cohesin organizes genome folding through loop extrusion, a process regulated by cofactors including NIPBL and PDS5. Recent studies by Wutz et al. and Shah et al. demonstrate that NIPBL promotes loop expansion in mammalian cells, whereas PDS5 restricts loop growth by facilitating NIPBL dissociation from cohesin. Together, these findings reveal a finely tuned mechanism governing genome folding.

Transcription elongation by RNA polymerase II (Pol II) was originally considered as the monotonic addition of ribonucleoside triphosphates to the growing nascent RNA chain. However, multiple lines of evidence now indicate that transcription elongation is a regulatory hub in gene expression that requires an increasing number of elongation factors (EFs), dysregulation of which leads to pathologies. In this review, we provide a current view of the elongation phase of Pol II, focusing on mammalian cells. We describe the increasing complexity of the mechanisms that control transcription elongation. We examine the growing set of EFs, their functional roles, and their systemic implications in human disease. Finally, we discuss the emergence of EFs as promising therapeutic targets.

By inducing a targeted and acute electromagnetic arrest of ependymal cell cilia beating in vivo, Bressan et al. demonstrates that mechanical forces generated by cilia beating enforces adult neural stem cell quiescence through mechanosensitive channels and downstream intracellular Ca2+ signaling.

Cancer immunotherapy is frequently hindered by the immunosuppressive tumor microenvironment. Although metal ions have been viewed as essential nutrients or cytotoxic payloads, emerging evidence reveals that they are potent immune modulators that orchestrate the cancer-immunity cycle. Here, we synthesize how ionic competition dictates immune cell plasticity and metabolic fate. We detail how metal ions regulate cell death pathways and immune signaling cascades, including the cyclic GMP-AMP synthase–stimulator of interferon genes and nuclear factor kappa B pathways, as well as immunological synapse formation and immune cell responses. Finally, we evaluate the clinical potential of targeting the metal ions–immune axis, from metallomic biomarkers, including Zrt-/Irt-related protein transporters and ion channels, to metallo-immunotherapy strategies. This framework provides a mechanistic roadmap for developing combination therapies to overcome immunotherapy resistance and harness the cellular metallome for precision oncology.

In the nervous system, aging causes deterioration of cellular and molecular processes that are associated with declines in cognition, sensory perception, and motor coordination. Aging is also the strongest risk factor for neurodegenerative disease, yet the mechanisms by which aging predisposes neurons to dysfunction remain incompletely understood. While genomic instability, proteostasis decline, mitochondrial dysfunction, and chronic inflammation have dominated prevailing models, recent evidence highlights RNA dysregulation as a central component of age-associated decline. In this review, we summarize recent findings suggesting that aging progressively erodes RNA regulatory fidelity through alterations in RNA-binding protein abundance, localization, biophysical behavior, and RNA interactions. We argue that age-dependent RNA dysregulation represents an important mechanism that converges with genetic risk to drive neuronal vulnerability and neurodegeneration.

Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associated sorting of NAC53/78 toggles these transcription factors between ER-associated degradation and nuclear activation, coupling proteasome induction to repression of photosynthesis-associated genes during stress.

The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.

Discovered in the 1970s, nuclear lamins control chromatin organization and are linked to many diseases. Zhang et al. now find that lamin A/C quantitatively constrains DNA replication initiation by limiting chromatin accessibility and sequestering proliferating cell nuclear antigen, extending lamin’s long-known role in replication to the control of origin firing.

The spindle assembly checkpoint (SAC) promotes mitotic fidelity by delaying anaphase until all kinetochores are stably attached to spindle microtubules. SAC silencing is increasingly recognised as a dynamic, sensitive process involving multiple molecular events at individual kinetochores. In Cell Reports, Conway et al. reveal how these events sequentially unfold.

Endoplasmic reticulum exit sites (ERES) are dynamic platforms that coordinate not only protein trafficking but also protein quality control and signaling functions. ERES size, composition, architecture, interactions, and activity must be precisely remodeled in response to myriad pathophysiological cues to finely tune cellular homeostasis. However, the molecular mechanisms underlying this regulation remain incompletely understood. Coat protein complex II (COPII) mediates many ERES functions, and its subunits and client cargos are subject to spatiotemporal regulation by post-translational modifications (PTMs) that modulate ERES assembly, cargo selection, and inter-organelle communication. In this article, we review recent advances in understanding how PTMs control the organization and functional versatility of ERES and the COPII system.

Homologous recombination repairs DNA double-strand breaks by copying genetic information from an intact DNA template, but how the homologous sequence is located within the vast 3D genome remains unclear. In this forum, we discuss how cohesin, a key chromatin organizer, guides the homology search during DNA repair in mammalian cells.

The endothelial barrier provides a defense against bacterial pathogens. Muenkel et al. show that endothelial barrier function increases when macrophages interact with endothelial cells. Conversely, infected macrophages decrease endothelial barrier function and transmigrate more efficiently. These findings show that the endothelium is biomechanically responsive to the infection status of macrophages.

Nuclear CGAS has previously been shown to promote tumor progression by inhibiting DNA repair. Recent data from Zhang et al. demonstrate that, upon phosphorylation by PKCα, CGAS translocates to the nucleus and initiates a CTNNB1-dependent program supporting metastatic dissemination. Thus, nuclear CGAS emerges as a multifaceted driver of cancer progression.

Vitamins are essential micronutrients traditionally viewed as passive cofactors that sustain cellular homeostasis. Emerging evidence challenges this notion, identifying vitamins as active regulators of cell fate that tune the threshold for regulated cell death. Through coordinated control of redox balance, metabolic pathways, and signaling networks, vitamins shape cellular susceptibility to diverse death programs. Their effects are highly context-dependent, enabling both prosurvival and prodeath outcomes depending on dose, cell type, and metabolic state. Recent studies further uncover noncanonical mechanisms linking vitamins to lipid remodeling, membrane trafficking, and organelle integrity. Collectively, these advances establish vitamins as dynamic modulators of cellular vulnerability and highlight their potential as therapeutic targets for selectively manipulating cell death in disease.

Heat stress reshapes plant transcriptomes through alternative splicing, yet the regulatory logic governing isoform switching remains poorly understood. Recently, a heat-activated, branch-point-dependent splicing switch in Serine/arginine-rich splicing factor 45a (SR45a) was uncovered by Xu et al. This switch couples transcriptional activation to isoform remodeling, driving thermotolerance.

Cultured mouse embryonic stem cells can be maintained in a naïve pluripotent state, meaning the cells can give rise to all lineages of the embryo proper while self-renewing through rapid proliferation. This review summarizes recent advances in our understanding of the role of the microtubule (MT) cytoskeleton in pluripotency maintenance. We focus on intercellular bridge MTs, as these are prominent, long-lasting structures that arise during cytokinesis yet maintain the connection between dividing sister cells into the next cell cycle. We describe how MT stability sets cytokinesis duration and how this may influence pluripotency maintenance, division symmetry, midbody inheritance, and abscission. Together, these findings highlight an emerging paradigm: MTs are not merely structural scaffolds but active players in stem cell maintenance.

Maintaining the proper balance between stem cell self-renewal and differentiated progeny production is essential for tissue development. Li et al. (2026) uncover a novel post-transcriptional mechanism that fine-tunes Notch signalling in Drosophila neural progenitors to preserve this balance, expanding the growing repertoire of RNA-binding proteins implicated in neural lineage progression.

Lipids are fundamental organizers of biological membranes, yet visualizing lipid species within subcellular organelles has remained beyond experimental reach. Lennartz et al. introduce Lipid-correlative light and electron microscopy (CLEM), a CLEM workflow that maps lipid species onto membrane ultrastructure with nanoscale precision, uncovering active sphingomyelin sorting within the early endosome.

Circular RNAs (circRNAs) are covalently closed, stable RNA molecules with broad physiological functions. Precise regulation of circRNA turnover is essential for cellular homeostasis. A recent study by Deng et al. uncovers an evolutionarily conserved mechanism in which RNAseK and the lysosome act synergistically to degrade circRNAs across metazoans.

Long noncoding RNAs (lncRNAs) regulate the tumor microenvironment (TME), yet their cell-intrinsic roles within immune populations of the TME remain underappreciated. In this review, we shift focus from the cancer cell to the immune compartment, systematically reviewing how immune cell-intrinsic lncRNAs govern CD8+ T cell exhaustion, CD4+ T cell polarization, NK cell cytotoxicity, dendritic cell antigen presentation, and macrophage inflammatory programming. We highlight lncRNAs that function as molecular switches—tipping immune cells between antitumor effector and immunosuppressive states—and examine how exosomal lncRNAs extend these regulatory circuits across cellular boundaries within the TME. Finally, we evaluate opportunities for lncRNA-based biomarkers and therapies designed to target the immune landscape, outlining a framework for integrating immune-intrinsic lncRNA biology into precision immuno-oncology.

Mobile genetic elements and their hosts engage in continuous evolutionary conflict. Marino et al. recently uncovered an unusual anti-CRISPR mechanism: the phage protein AcrVA2 triggers translation-coupled mRNA degradation by recognizing nascent Cas12. The findings suggest that nascent peptides may signal an underappreciated layer of gene regulation across the kingdoms of life.

Cytotoxic immunity has long seemed the exclusive province of blood. Chai et al. challenge this view by describing ruptoblasts, glandular cells that explode on hormonal cues to kill neighbors across kingdoms. Ruptosis, their distinctive form of death, hints at an ancient immune logic that mainstream model organisms appear to have quietly lost.

Do cells remember past mechanical experiences to prepare for future physical challenges? Holle et al. demonstrate that stiffness priming enhances confined migration through NFATC2-dependent programs. Beyond this specific mechanism, their work supports the emerging concept of mechanical memory as a hierarchy of interconnected cellular states operating across multiple timescales.

Nucleotide-binding leucine-rich repeat (NLR) receptors are ubiquitous intracellular sensors. Guo et al. recently revealed that the wheat CCG10-NLR, Wheat Autoimmunity 3, forms a previously undescribed plant octameric resistosome to mediate cell death and immunity. This discovery uncovers a distinct configuration, highlighting the remarkable structural plasticity in plant immune signaling.

Intercellular mitochondria transfer has emerged as a new form of cell-to-cell communication with profound consequences for cellular fate. A growing body of evidence defines mitochondria transfer between cells as a new pathological program in which cancer cells appropriate functional mitochondria from donor cells, thereby co-opting conserved physiological mechanisms of energy allocation to gain bioenergetic and phenotypic advantages. Our recent work demonstrates the prevalence of mitochondria transfer at the nerve–cancer interface, with neurons, though not exclusively, serving as a prominent source of the organelle. This suggests an unrecognized role of the nervous system in systemic energy redistribution and indicates that tumors may exploit this ancient, physiologically grounded mechanism to fuel progression and metastasis.

Bosveld et al. uncover how epithelial tissue buffers mitotic spindle errors. In the Drosophila notum, cells displaced by spindle misorientation either reintegrate via cell-autonomous and nonautonomous forces or are eliminated. This coordinated response links cell and tissue mechanics, Hippo-dependent survival signaling, and systemic tumor necrosis factor signaling-mediated apoptosis to maintain epithelial homeostasis.

Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.

The protease-activated receptor-1 (PAR1) exhibits biased agonism upon activation by the coagulant protease thrombin and the anticoagulant protease activated protein C. In a recent study, Gonzalez Ramirez et al. demonstrate that differences in receptor conformations, engagement of G protein-coupled receptor kinase 5, and receptor phosphorylation patterns govern the biased agonism at PAR1.

Multiciliated cells (MCCs) represent a complex cell type with a range of unique features. Jewett et al. identify a novel DNA damage response (DDR) that occurs during MCC differentiation. Inhibition of DDR blocks the formation of MCCs, indicating that this damage response is likely an important step in MCC differentiation.

Tackling scientific questions benefits from different points of view. Coleading a lab by two scientists may stimulate scientific discussion while also providing a different form of mentorship. Here, we share our experience in running a joint lab and discuss how this form of dual leadership contributes to collaborative science.

The bacterial-like identity of membranes in modern eukaryotes and the formation and disassembly of large hemifusion diaphragms during organelle fusion, remain unresolved problems in cell biology. In this forum, we comment on a noncanonical fusion pathway, supported by molecular simulations, which offers a unified physicochemical framework to rationalize these phenomena.

Whether astrocytes form selective long-range networks remains unresolved. Cooper et al. use connexin 43-TurboID to reveal region-specific, plastic astrocyte gap-junction networks that partly overlap yet are not reducible to canonical neuronal projections. We discuss how this work refines the concept of astrocyte syncytial coupling and expands models of inter-regional brain connectivity.

Reactive oxygen species (ROS) function as both damaging and signaling molecules by modifying macromolecules. Advances in proteomics have greatly expanded the identification of ROS target proteins, demonstrating redox modifications as a dominant form of post-translational regulation. However, determining which of these modifications are regulatory and impact protein function remains a key challenge in the field. In this opinion article, we discuss the promise and peril of prioritizing ROS targets identified by proteomics solely based on the highest levels of oxidation for downstream scrutiny. We argue for the integration of functional genomics as a systematic and orthogonal approach for connecting redox-based protein modifications with functional outcomes. This combined approach accelerates the discovery of novel ROS- and other metabolite-modified signaling pathways.

Alternative lengthening of telomeres (ALT) is a recombination-mediated telomere maintenance mechanism. Although the core ALT machinery is defined, the initiating events remain unresolved. Taylor et al. demonstrate that telomeric heterochromatin enrichment drives nuclear compartmentalization, promyelocytic leukemia body nucleation, and telomere clustering, establishing a chromatin-defined environment that is permissive for recombination.

Neural stem cells (NSCs) span a continuum of cellular states that share fundamental properties with their differentiated glial progeny. Recent single-cell studies have refined our understanding of the diversity within both NSC and glial populations, revealing a highly dynamic and interconnected landscape of cell identities. In this review, we examine the glial nature of NSCs, emphasizing their heterogeneity and the stem- and progenitor-like properties shared with the differentiated glia. We focus particularly on astrocytes and integrate evidence from invertebrate models demonstrating that glial cells possess an intrinsic capacity for neurogenesis. Together, these findings highlight areas of convergence between astrocyte plasticity and NSC-associated properties, with important implications for nervous system regeneration and brain cancer.

Neuronal size varies across evolution, diseases, and brain regions. It has long been regarded as a descriptor, not a driver of function. Using triploid Xenopus, Liu et al. show that neuronal enlargement remodels neurite geometry, reduces proliferation, increases phospho-extracellular signal regulated kinase (pERK) responses, and alters behavior, linking cellular scaling to brain function.

Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.

Co-directional (CD) transcription–replication conflicts (TRCs) arise when the DNA replication and transcription machineries progress along the same DNA template. Although generally considered less severe than head-on (HO) TRCs, CD TRCs are now recognized as frequent and actively regulated events that influence genome stability. The Cullin 3–Potassium channel tetramerization domain containing 10 (KCTD10) ubiquitin ligase complex functions as a bivalent sensor that detects CD collisions and directs the nonproteolytic ubiquitination of the elongation factor TCEA2, transiently remodeling RNA polymerase II to permit replisome bypass. This sensing-driven remodeling reframes CD TRCs as dynamic decision nodes where replication and transcription priorities are continuously negotiated, highlighting how conflict geometry, ubiquitin signaling, and genome maintenance are functionally integrated.

Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed ‘Mitochondrial Safeguard (MitoSafe)’, in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.

The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.

Errors in transcription and RNA processing generate aberrant transcripts that can produce truncated, nonfunctional, or dominant-negative proteins. RNA surveillance pathways, centered on the RNA exosome, recognize diverse processing defects and initiate targeted RNA degradation. These mechanisms also regulate the short half-life of chromatin-associated noncoding RNAs through co- and/or post-transcriptional degradation. This review examines how the RNA exosome achieves substrate specificity, focusing on its interactions with the helicase cofactors mRNA transport 4 (MTR4) and superkiller 2 (SKIV2L) and the modulatory role of RNA modifications such as N6-methyladenosine. The broad spectrum of RNA exosome targets underscores its central functions in transcription, translation, genome integrity, and cell fate determination.

Telomere crisis contributes to cancer genome evolution. Beyond the loss of end protection, replication defects at short telomeres give rise to aberrant fork intermediates that can be resolved by microhomology-mediated end joining. Such mutagenic repair yields chromosomal fusions and complex rearrangements that shape cancer genomes.

Endoplasmic reticulum (ER)-resident ubiquitin ligases are essential to cellular homeostasis and diverse signaling pathways, functioning in protein quality control, lipid metabolism, innate immunity, and interorganelle communication. While best known for their roles in ER-associated degradation (ERAD) of misfolded proteins, accumulating evidence shows that they also mediate the regulated turnover of functional ER proteins and contribute to ER-phagy, thereby expanding their roles in ER homeostasis. This review summarizes recent advances in understanding substrate recognition mechanisms employed by ER ubiquitin ligases and how these enzymes coordinate ERAD and ER-phagy, with a primary focus on mammalian systems. We further discuss their roles in ER homeostasis and immune responses, and how their dysregulation contributes to diseases such as neurodegeneration and immune disorders.

The cleavage of full-length transfer RNAs generates functional small RNAs called tRNA-derived small RNAs (tsRNAs or tDRs). This review synthesizes recent advances in our understanding of tDRs, summarizing the molecular mechanisms of their biogenesis and illuminating their function in modulating pathways important in the cellular stress response. Key structural motifs appear to be critical determinants of tDR function by modulating binding to partner proteins and RNAs. Finally, the role of tDRs in the pathogenesis of various diseases and the feasibility of targeting them with novel molecular tools are discussed. In summary, tDRs are an evolutionarily conserved class of small RNAs important for the cellular response to stress and are emerging as a promising target for human diseases.

Within the cell nucleus, non-DNA structures called nuclear bodies interact with chromatin to regulate gene expression and organize our genetic material. Among nuclear bodies, nuclear speckles are prominent. They interact with broad genomic regions, serve as major gene-activating structures, and are implicated in viral infection, cancer, neurodegeneration, stress response, and development. Advances that integrate genomics with imaging are leading to a deeper understanding of how nuclear speckles fit into our current knowledge of chromatin biology, genome organization, and the central dogma of biology. Collectively, these recent studies emphasize nuclear speckles as key gene regulatory structures within the cell nucleus, offering new perspectives on how gene expression dysregulation is linked to disease.

The mechanism of molecular passage through nuclear pore complexes (NPCs) remains debated between passive diffusion and constrained transport. Integrating single-particle tracking, cargo-centric ensemble assays, and fluctuation analyses reveals that productive transport events are rapid, spatially confined, and biased, supporting a convergent phenomenology that provides an integrated view of NPC transport.

Although senescent cells are commonly characterized by stable cell cycle arrest, emerging evidence indicates that senescence is not a uniform state but a collection of highly heterogeneous phenotypes. This heterogeneity stems from biological factors, such as diverse senescence markers, cellular origins, and targeting mechanisms, as well as from technical variations in experimental approaches, notably in the design of transgenic mouse models. By summarizing recent advances in next-generation senolytic strategies, multiomics profiling, and genetically engineered mouse models of senescence, we provide an integrated perspective on the origins and consequences of senescent cell heterogeneity. Such a perspective is essential for refining investigative methodologies and for developing precise therapies that selectively target senescent cell populations whose roles have been experimentally validated in vivo.

Heme-regulated eukaryotic translation initiation factor 2 alpha kinase (HRI) is highly expressed in red blood cell precursors and plays a critical role in their maturation by coupling globin synthesis to heme availability. HRI plays critical roles in responding to cytoplasmic and mitochondrial unfolded proteins, oxidative stress response, innate immunity, neurobiology, and the suppression of epithelial cancers. HRI activity is regulated by multiple signaling networks, which, in turn, modify cellular homeostatic responses. In this review, we summarize emerging evidence on the role of HRI in normal biology and pathobiology, the molecular underpinnings of HRI’s regulation, and discuss chemical modifiers of HRI, which may form the basis of drug development programs for the treatment of human disorders whose pathobiology can be modified by HRI.

Adaptations to changing environments manifest in various cellular activities across multiple timescales, where single-cell responses can occur asynchronously between individual cells. Hence, accurate delineation of transient or rare activities often requires real-time monitoring of single cells over hours or days. While great strides have been made in the throughput of molecular analysis methodologies, most biochemical methods are cell destructive and, therefore, can only provide snapshots of dynamic processes. Noninvasive observations of natural cell behaviors offer unique insights into key dynamic events. In this feature review article, we discuss current toolkits for monitoring real-time dynamics of diverse cellular activities in living cells, as well as their advantages and challenges. We also speculate on new avenues for noninvasive single-cell monitoring that will be feasible in the foreseeable future.