Pancreatic cancer is a highly aggressive and lethal malignancy with an exceptionally poor prognosis. Its clinical management is severely hampered by insidious early symptoms, strong invasiveness, intrinsic chemoresistance, and limited efficacy of conventional therapies. Carbon dots (CDs) have shown great promise in precision cancer theranostics owing to their excellent optical properties, high biocompatibility, controlled drug loading and release capabilities and customizable targeting features. This review critically examines the major therapeutic barriers in pancreatic cancer management, systematically summarizes the applications of CDs in pancreatic cancer imaging, targeted drug delivery, hyperthermia and pH-responsive theranostics, analyzes the current limitations of CD-based nanosystems, and discusses future development directions. This work aims to provide a rigorous theoretical foundation for the rational design and development of novel CD-mediated precision intervention strategies for pancreatic cancer.

DNA replication and transcription operate on the same chromatin template and inevitably interfere with one another, giving rise to transcription-replication conflicts (TRCs), an important endogenous source of replication stress and genome instability. Although head-on (HO) conflicts are generally more disruptive than co-directional (CD) encounters, orientation alone does not determine the outcome. Gene architecture, transcriptional activity, replication timing, chromatin environment, DNA topology, and R-loop dynamics can all influence whether an approaching replication fork pauses, collapses, or traverses a transcribed region. Recent single-molecule, genomic, and biochemical studies further suggest that some CD encounters can be traversed under favorable topological and transcriptional conditions, although the mechanisms that permit such bypass and their broader biological significance remain incompletely understood. Here, we discuss TRC control within an operational framework comprising prevention, resolution, tolerance, and recovery. We examine how cells coordinate replication and transcription in space and time, regulate R-loop formation and turnover, protect or remodel challenged forks and chromatin, and modify or remove transcription complexes at conflict sites. We also consider how emerging single-molecule and multi-omic approaches can distinguish transient fork pausing from persistent pathological conflicts. Finally, we discuss the contributions of TRCs to cancer-associated chromosomal instability, cellular senescence, and neurodegenerative disease, and highlight the questions that must be resolved to understand how cells preserve genome integrity when replication and transcription compete for the same DNA template.

DNA replication constantly faces obstacles that threaten genome stability. Faithful duplication requires replication forks to smoothly process template damage, chemical or topological blocks, and repair intermediates. Traditionally, replication-associated lesions are described by their initial structures (nicks, gaps, etc.). However, their S-phase identities are highly transitional: a template single-strand break (SSB) can become a one-ended double-strand break (DSB) upon fork arrival, a replication fork stalled by a template block can reverse, restart, or collapse, and a repriming event leaves a post-replicative single-stranded DNA (ssDNA) gap. The biological consequence of a lesion depends heavily on its structural transitions and how it is "routed" through distinct repair, bypass, or cleavage pathways. In this review, we shift our focus from static structural identities to dynamic lesion routing, emphasizing the coordination between SSB repair (SSBR) and DSB repair (DSBR). We first summarize the major sources of replication-associated strand lesions, and then discuss how strand lesions are managed across three processing windows: SSBR before fork encounter, the overlap zone in which gaps and stressed forks can be buffered without immediate DSB conversion, and broken-fork/DSBR-centered processing after DSB formation, including homologous recombination (HR)-mediated restart, break-induced replication (BIR)-like synthesis, or end joining. Depending on the routing network, lesion processing can result in accurate completion, delayed resolution or salvage, mutagenic completion, structural genome scars, or cytotoxic genome instability. Finally, we discuss how this dynamic framework refines our understanding of DNA damage response (DDR)-targeted cancer therapies, drug resistance, and treatment outcomes in different genetic or therapeutic contexts.

The tumor immune microenvironment (TIME) is a principal determinant of tumor progression, metastatic dissemination, and therapeutic response. Cellular senescence, primarily through the senescence-associated secretory phenotype (SASP), progressively reshapes the TIME toward immunosuppressive and therapy-resistant states. Here, we propose an integrative framework of “senescence-associated transcriptional reprogramming” comprising three mechanistic layers: endogenous inflammation-driven signaling centered on the cGAS-STING-NF-κB-IFN hub; lineage-specific epigenetic lock-in in immune cells; and metabolic-epigenetic coupling. We further discuss mechanism-guided, temporally optimized senolytic and senomorphic strategies, particularly relevant to elderly cancer patients, to rationally reverse senescence-driven tumor immune tolerance and enhance current immunotherapies.

The tumor immune microenvironment (TIME) is a central determinant of cancer progression and therapeutic response. Although organoid and organ-on-a-chip technologies have substantially advanced the modeling of tumor-immune interactions, most current platforms overlook a critical dimension of clinical reality: immunosenescence. This process profoundly reshapes immune cell composition, functional capacity, and tumor-immune crosstalk, yet it remains largely absent from existing in vitro systems. In this review, we provide a conceptual and methodological overview of organoid- and microfluidic-based models for reconstructing the TIME. We highlight their respective strengths in capturing tumor heterogeneity and dynamic immune processes, while critically evaluating their limitations in modeling long-term immune evolution and age-associated dysfunction. Importantly, we propose immunosenescence as a missing but essential modeling axis and argue that it should be treated as a controllable experimental variable rather than a background condition. By integrating aging-associated immune features into advanced 3D and microfluidic platforms, next-generation models are poised to better recapitulate patient heterogeneity and improve the prediction of immunotherapy outcomes. This perspective underscores a shift toward age-aware, physiologically relevant tumor models and provides a framework for advancing precision immuno-oncology in an aging population.

The rising incidence of age-related brain pathologies, including brain malignancy, underscores an urgent need to understand the mechanistic interplay between aging and tumorigenesis. Historically viewed as distinct entities, brain tumors and neurodegenerative disorders are now recognized to share key biological processes, such as cellular senescence, chronic inflammation, and metabolic dysregulation. In this review, we deconstruct the existing knowledge at the intersection of cancer neuroscience and aging biology, and propose that age-related alterations in neuronal function, such as the accumulation of senescent cells, ion channel dysregulation, and neurotransmitter imbalance, are not inert background features but as active mediators of tumor progression and treatment resistance. We summarize the aged neural microenvironment, marked by a proinflammatory senescence-associated secretory phenotype (SASP) and blood-brain barrier dysfunction, underlies a permissive soil for malignancy. Moreover, we highlight the emerging concept that tumors can induce a pathological aging phenotype in surrounding neurons, which in turn potentiates the observed cognitive deterioration. By framing brain tumors as products of a dysfunctional aging ecosystem, we propose therapeutic strategies that target convergent aging mechanisms through senolysis, metabolic reprogramming, and neurotransmitter modulation may simultaneously achieve tumor control and preserve cognitive function. This integrated perspective opens new avenues for repurposing neuroactive drugs and designing interventions that address the sophisticated biology of the aging brain and malignancy.

Aging remains the primary risk factor for malignancy, driven primarily by the progressive decline of the immune system known as immunosenescence. Natural killer (NK) cells serve as the critical effectors of tumor immunosurveillance, yet their anti-tumor efficacy is compromised during biological aging. This review delineates the multifaceted mechanisms of NK cell immunosenescence including phenotypic subset redistribution, receptor signaling dysregulation, and metabolic biogenesis failure driven by mitochondrial impairment alongside telomere attrition and p16 p21 mediated cell cycle arrest. These cell intrinsic defects interact with the suppressive aging microenvironment to create a self-reinforcing vicious cycle that facilitates tumor escape in the elderly population. Breaking this cycle necessitates a multi-dimensional therapeutic framework that integrates cellular rejuvenation via induced pluripotent stem cell (iPSC) derived chimeric antigen receptor (CAR) NK cells with niche remodeling using senolytics or bone marrow rejuvenation. Ultimately targeting the biological hallmarks of NK cell immunosenescence represents a significant frontier in geriatric oncology offering the potential to resuscitate anti-tumor immunity for the burgeoning elderly population.

Homologous recombination (HR) is a high-fidelity DNA repair pathway that preserves genome stability through the accurate repair of DNA double-strand breaks. RAD51 is the central recombinase of HR and catalyzes the key processes of homology search and strand invasion through the formation of nucleoprotein filaments on single-stranded DNA. The assembly, stability, and disassembly of RAD51 filaments are tightly regulated by a complex network of mediators, cofactors, and anti-recombinases, ensuring efficient DNA repair while preventing aberrant recombination. Beyond its canonical role in HR, RAD51 also contributes to replication fork protection and replication stress responses. Dysregulation of RAD51 activity can lead to genome instability, cancer development, hereditary disorders, and cellular senescence. Conversely, elevated RAD51 expression frequently promotes therapeutic resistance in tumors. In this review, we summarize the molecular mechanisms of RAD51-mediated HR repair, discuss the regulatory pathways that control RAD51 activity and dynamics, examine its roles in genome stability and human disease, and highlight recent advances in therapeutic strategies targeting RAD51 and the HR pathway. Understanding the multifaceted functions of RAD51 will facilitate the development of more effective DNA repair-directed cancer therapies.

Cellular senescence is a stress-induced cell-cycle arrest program accompanied by the senescence-associated secretory phenotype (SASP). While senescent cells are typically eliminated through immune surveillance under normal physiological conditions, they tend to accumulate progressively during aging and in chronic diseases. This review summarizes current evidence suggesting that such persistence is attributable not only to immune system decline but also to active, cell-intrinsic mechanisms of immune evasion. We discuss how senescent cells escape clearance by weakening immune recognition, suppressing phagocytic removal, resisting apoptosis, remodeling the inflammatory and structural microenvironment through SASP, and activating inhibitory checkpoint pathways in aged tissues. Furthermore, we investigate the contribution of these mechanisms to representative age-related diseases across multiple organs. Finally, we highlight emerging therapeutic strategies aimed at targeting the immune evasion of senescent cells, including checkpoint modulation, chimeric antigen receptor (CAR)-based cell therapies, vaccination approaches, and other immune-bypass strategies. Collectively, these insights underscore immune evasion as a critical determinant of senescent cell persistence and a promising target for interventions in aging and age-related diseases.

DNA integrity and stability are intricately linked to DNA damage repair (DDR) pathways, which have long been well characterized through a biochemical perspective. However, the physical properties of the nucleus in which DNA damage occurs have been long overlooked, leaving the relationship between nuclear mechanics and DDR poorly defined. In this review, we describe the core mechanical components, including the lamina, chromatin, and linker of nucleoskeleton and cytoskeleton (LINC) complex, which collectively determine nuclear stiffness, tension, and structural integrity. We further define the regulatory role of nuclear mechanics in DDR, with particular emphasis on DNA double-strand break (DSB) repair. Aberrant nuclear stiffening, tension, and envelope rupture may cause persistent DNA repair failure and genomic instability. Nuclear mechanics are aberrantly altered in cancers, therefore manipulating nuclear mechanics may counteract therapeutic drug resistance via regulating DDR efficiency in cancer cells. Throughout, we conclude that nuclear mechanics acts as a physical rheostat for DDR. Manipulating nuclear stiffness, tension, or envelope integrity susceptibility offers a new therapeutic axis for sensitizing tumors to DNA-damaging agents.

The microenvironment of solid tumors is characterized by dynamic availability of oxygen and persistent, complex inflammatory signaling. Accumulating evidence suggests that hypoxia and inflammation actively influence tumor progression and therapeutic response. In physiological conditions, hypoxic and inflammatory responses function as evolutionarily conserved protective mechanisms. Acute hypoxia promotes temporary metabolic adaptation to preserve tissue viability, while acute inflammation facilitates clearance of damaged or abnormal cells and restores homeostasis. In tumors, by contrast, hypoxia and inflammation become chronic and unresolved. Persistent activation of these protective signals gradually renders the microenvironment permissive to the sustained adaptation of abnormal cells rather than eliminating them. This transition from clearance to tolerance reshapes cellular metabolism, immune cell behavior, and tissue organization within the tumor microenvironment. As a result, tumor cells increasingly adapt to metabolic stress and evade effective immune surveillance, contributing to malignancy and therapy resistance. Interestingly, some subterranean species, including the naked mole rat and blind mole rat, show natural cancer resistance. They either evolved adaptations counteracting inflammation, or take the immune response to their advantage to prevent cancer. These anti-cancer mechanisms are a result of adaptation to their hypoxic subterranean habitats. In this review, we examine the fundamental features of hypoxia and inflammation in tumors, explore their functional interplay, and discuss how these mechanisms are evaded or harnessed by cancer resistant subterranean mammals. We further propose a simple clearance to resistance framework that links acute protective stress responses, chronic tumor-promoting adaptation, and naturally evolved cancer resistance.

Aging and cancer reflect distinct but interconnected manifestations of cellular stress responses shaped by context-specific molecular and environmental factors. Senescence initially restrains malignancy through stable cell-cycle arrest and immune clearance, yet persistence of senescent cells and the senescence-associated secretory phenotype (SASP) paradoxically drives tumor progression, therapeutic resistance, and immune evasion via chronic inflammation and metabolic reprogramming. Functional genomic screening has evolved from bulk RNA interference to precision clustered regularly interspaced short palindromic repeats (CRISPR) modalities, including knockout, interference, activation, and base editing, and onward to single-cell and in vivo platforms. These technological advances have transformed our capacity to dissect cellular state transitions and network dependencies with unprecedented resolution. Here, we trace this technological evolution and synthesize its impact on aging and cancer research, with emphasis on chromatin regulation, metabolic rewiring, the SASP, nucleocytoplasmic transport, therapeutic response, and the tumor microenvironment. We emphasize that the current evidence derives predominantly from preclinical functional screens and computational predictions. We propose shifting from gene-centric discovery toward context-dependent network analysis. Integrating precise editing, in vivo screening, single-cell multi-omics, and emerging artificial intelligence (AI)-assisted design may provide information and a design basis for future combined strategies that simultaneously target vulnerabilities in senescent cells and malignant populations.

Cancer recurrence remains a leading cause of mortality in patients with solid tumors. Early disseminated tumor cells (DTCs), which seed distant organs during the initial stage of tumor progression, are widely recognized as an important source of late metastatic relapse. Tumor cell dormancy, a reversible but prolonged non-proliferative state, enables DTCs to survive in metastatic tissues for years or even decades before re-entering the cell cycle and giving rise to overt metastases. Accumulating evidence indicates that dormancy is regulated by both cell-intrinsic mechanisms, such as epigenetic reprogramming and metabolic adaptation, and extrinsic cues from the tissue microenvironment. Among these extrinsic regulators, ageing has emerged as a critical determinant of DTC fate by profoundly remodeling tissue microenvironments through cellular senescence, chronic inflammation, extracellular matrix (ECM) remodeling, vascular dysfunction, stromal metabolic rewiring, and immune dysregulation. These ageing-associated alterations progressively erode dormancy-supportive niches, thereby leading to metastatic reactivation. In this Review, we summarize the molecular mechanisms governing tumor dormancy and discuss how ageing-associated microenvironmental remodeling contributes to the reactivation of dormant DTCs. We highlight the roles of the senescence-associated secretory phenotype (SASP), ECM remodeling, vascular deterioration, and organ-specific stromal ageing in regulating the maintenance and exit of tumor dormancy. We also discuss emerging translational opportunities, including dormancy-reinforcing therapies, senolytic strategies, liquid biopsy-based surveillance, and advanced experimental platforms such as single-cell and spatial technologies. Collectively, this Review provides a conceptual framework for understanding how ageing progressively modulates tumor dormancy and highlights potential strategies to prevent late metastatic recurrence.

Homologous recombination (HR) is a high-fidelity DNA double-strand break repair pathway that plays a central role in preserving genome stability and suppressing tumorigenesis. Core HR proteins, including CtIP, BRCA1, and RAD51, function in a tightly coordinated manner to mediate DNA end resection, pathway choice, and homology-directed strand exchange. Increasing evidence indicates that the abundance, activity, and chromatin engagement of these HR regulators are not constitutive but are dynamically controlled across multiple regulatory layers, including transcriptional programs, post-transcriptional RNA regulation, and post-translational proteostasis mechanisms. These regulatory systems integrate cell-cycle, stress signaling, and metabolic context to regulate HR capacity. In this review, we present an integrated framework describing how CtIP, BRCA1, and RAD51 are regulated across transcriptional, post-transcriptional, and post-translational levels, with an emphasis on mechanisms that jointly control multiple HR proteins as well as gene-specific regulatory modules.

YWHAG is a subtype of the 14-3-3 protein family that regulates the transduction of multiple signaling pathways in cells, such as the phosphoinositide 3-kinase–protein kinase B (PI3K-AKT) and mitogen-activated protein kinase (MAPK) pathways, by recognizing and binding to specific phosphorylated target protein motifs. These signaling pathways are widely found to be abnormally activated or shut down in human diseases, such as cancer and neurodegenerative diseases. Different evidence has shown that the expression levels and functions of YWHAG in different tumors are not the same. Meanwhile, the potential functions of YWHAG in these diseases and its role in regulating abnormal signaling pathways are still unknown. Therefore, further exploration and research are needed to determine YWHAG’s core role in regulating signaling pathways and whether YWHAG can be a therapeutic target for diseases to develop corresponding drugs. This review will revisit the structure and function of YWHAG, elaborate on the newly identified YWHAG-interacting proteins in recent years, summarize the functions of YWHAG in cancer while comparing it with the homologous family member YWHAZ, explore the functions of YWHAG in neurodegenerative diseases, and present our perspectives on drug-screening strategies targeting YWHAG.

Skin photoaging is a progressive, ultraviolet (UV)-driven form of extrinsic skin aging that compromises epidermal barrier integrity, dermal extracellular matrix organization, pigmentary homeostasis, and subcutaneous tissue support. Current findings indicate that photoaging is driven by interconnected molecular mechanisms, including ultraviolet A-(UVA)- and ultraviolet B (UVB)-induced reactive oxygen species (ROS) generation, DNA photolesions, mitogen-activated protein kinase/activator protein-1 (MAPK/AP-1-) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammatory signaling, matrix metalloproteinase activation, collagen and elastin degradation, mitochondrial dysfunction, autophagy impairment, and senescence-associated secretory phenotypes (SASP). Plant-derived polyphenols, carotenoids, and terpenoids primarily attenuate oxidative stress and inflammatory signaling; marine-derived mycosporine-like amino acids, sulfated polysaccharides, xanthophylls, and collagen peptides provide UV absorption, matrix protection, and structural support; and microbiome-derived metabolites and probiotics modulate redox balance, immune signaling, and barrier homeostasis via the gut-skin axis. By integrating layer-specific pathogenesis with multi-source natural interventions, this review highlights translationally relevant strategies for developing safer, mechanism-guided anti-photoaging therapies, informing both preclinical research and clinical applications.

Cellular senescence is a cell fate triggered by diverse endogenous and exogenous stresses, including DNA damage, telomere dysfunction, and metabolic dysregulation. It is characterized by irreversible cell cycle arrest and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). As a hallmark of ageing, senescence contributes to various physiological processes and is closely associated with the pathogenesis of age-related diseases. Specifically, senescent cells secrete SASP factors, which promote chronic inflammation, and propagate senescence to neighboring normal cells. DNA damage, a crucial inducer of cellular senescence and inflammation, often leads to the accumulation of cytosolic DNA. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway has emerged as a critical mechanism for detecting such intracellular DNA, and its excessive activation is strongly associated with senescence and age-related chronic inflammation (inflammaging). Accumulating evidence indicates that multiple factors can trigger cGAS-STING signaling, thereby stimulating inflammatory responses and accelerating cellular senescence. In this review, we summarize recent advances in understanding how cGAS-STING signaling orchestrates cellular senescence and inflammaging. We outline the key hallmarks and triggers of cellular senescence, with particular emphasis on the role of cGAS in age-related inflammatory diseases. Finally, we discuss that targeting the cGAS-STING pathway may pave new ways for therapeutic strategies to mitigate cellular senescence-associated diseases.

Operating as a physically and physiologically integrated unit, skeletal muscle and bone are fundamental to human mobility and metabolism. Their reciprocal crosstalk endures throughout life. In early embryonic development, with a primary focus on morphogenesis, skeletal muscle and bone actively drive the functional maturation of both tissues during development. When the interplay reaches relative homeostasis during adulthood, they reciprocally sustain the functional integrity and physiological homeostasis of one another. With aging, however, this intimate connection exacerbates reciprocal decline, initiating a pathological feed-forward loop that precipitates osteosarcopenia. As this crosstalk is orchestrated by a shifting matrix of mediators, from biomechanical loads to neuronal, immunological, and secretory signals, understanding their age-associated alterations may help provide a point of intervention for treatment. This review outlines dynamic changes in muscle-bone crosstalk throughout the lifespan, discusses longitudinal changes in aging, and provides stage-specific perspectives for intervention.

Aging is a key risk factor for cancer, with complex, context-dependent processes influencing both tumor initiation and progression. While certain aging-associated processes restrain cellular proliferation, others drive tumor initiation and progression, revealing a context-dependent duality in the role of aging in cancer. Increasing evidence indicates that many of these transitions occur not through genomic alterations, but through reprogramming of protein post-translational modifications (PTMs). Phosphorylation, ubiquitination, acetylation, methylation and an expanding repertoire of acylations collectively regulate protein activity, stability, localization and interactions, translating aging-associated stresses, including metabolic imbalance, microenvironmental remodeling and accumulated damage, into functional cellular outcomes. In this review, we examine how PTMs bridge aging and cancer through three interconnected axes: integration of stress signals, encoding of metabolic states, and modulation of the tissue microenvironment. We discuss how major PTM systems coordinate core cellular processes, such as checkpoint control, proteostasis, chromatin organization and cell–environment communication, and how, through dynamic and combinatorial actions, they establish distinct regulatory states that determine whether tissues sustain homeostasis, progress to dysfunction, or undergo malignant transformation. An in-depth understanding of how PTMs define these states provides valuable insights into disease stratification and offers new avenues for therapeutic interventions.

Oral stem cells (OSCs) represent a group of mesenchymal stromal/stem cell-like populations localized within dental and craniofacial tissues, where they play vital roles in maintaining tissue integrity and supporting regeneration. Although OSCs possess robust self-renewal capacity and multilineage differentiation potential, they progressively develop senescent phenotypes in response to organismal aging, prolonged in vitro culture, and adverse microenvironmental stimuli. The senescent state of OSCs is characterized by diminished proliferation and differentiation, genomic instability, mitochondrial impairment, and the establishment of a senescence-associated secretory phenotype. Mechanistically, OSC senescence arises from a series of interacting processes, including DNA damage, metabolic imbalance, epigenetic reprogramming, and persistent inflammatory signaling. These alterations drive stem cell functional decline and compromise the surrounding regenerative niche. Consequently, OSC aging is closely associated with multiple craniofacial disorders, including periodontal tissue breakdown, defective dentin-pulp regeneration, alveolar bone resorption, and delayed mucosal healing. To reverse these age-related changes, various rejuvenation approaches have been explored, including epigenetic modulation, metabolic intervention, senescence-targeting therapies, extracellular vesicle-mediated strategies, and biomaterial-based niche engineering. Nonetheless, translational challenges remain, particularly in cellular heterogeneity, donor-related variability, and age-dependent functional changes in extracellular vesicles (EVs). Future efforts are expected to focus on developing targeted and clinically translatable strategies to rejuvenate OSCs and enhance regenerative outcomes.

Mesenchymal stem cells (MSCs) hold substantial promise for treating aging and age-related diseases due to their regenerative and immunomodulatory properties. However, clinical applications remain limited by the poor survival and short retention of transplanted cells within the hostile aged microenvironment. Emerging genetic-engineering approaches, including viral vector-mediated genetic modification and genome-editing technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) systems, offer powerful strategies to enhance MSC resilience, functionality, and reparative capacity. Recent advances, such as the development of senescence-resistant mesenchymal progenitor cells (SRCs), demonstrate that precise modification of key longevity pathways can produce MSCs with superior stress resistance, reduced senescence, and improved regenerative performance in both rodent and non-human primate models. These findings highlight the potential of genetically enhanced MSCs as next-generation cellular therapeutics for precision interventions in aging. Nevertheless, challenges related to long-term safety, immunogenicity, off-target effects, and large-scale manufacturing must be addressed before clinical translation.

While genomic instability is a hallmark of aging, and unrepaired or mutagenic double-strand breaks (DSBs) are established drivers, recent evidence suggests that even accurately repaired DSBs contribute to aging. Here, we focus on an intriguing study by Bantele et al. published in Science, which demonstrates that Cas9-induced DSB repair can induce persistent, heritable alterations in higher-order chromatin structure and function, termed "chromatin fatigue". These alterations, characterized by changes in chromatin topology and gene expression, persist long after DNA sequence restoration and are inherited through cell divisions. Crucially, they impair transcriptional responsiveness to physiological stimuli. This finding provides a novel mechanism for DNA damage-driven aging independent of mutations, potentially explaining age-related epigenetic dysfunction. The commentary also highlights key unresolved questions regarding the permanence, locus-specificity, and physiological impact of chromatin fatigue, and explores its interaction with age-related DNA repair decline. This striking molecular phenomenon challenges the notion that faithful repair ensures full functional restoration and opens avenues for future research into interventions against aging and other age-related diseases, such as cancer.

Genomic instability (GI), characterized by the progressive failure of mechanisms that maintain genome integrity, serves as a fundamental link between aging and cancer at the molecular level. It not only drives the aging process but also promotes tumorigenesis through multiple pathways: on one hand, GI can induce cellular senescence and create a pro-inflammatory and tissue remodeling microenvironment via the senescence-associated secretory phenotype; on the other hand, GI can bypass senescence, directly facilitating tumor progression through mechanisms such as aneuploidy, the expansion of pre-malignant clones, and chronic inflammation mediated by DNA damage-associated molecular patterns. The decline in physiological functions accompanying aging and the increased risk of cancer are closely associated with the accumulation of GI, while aging itself may exert anti-cancer effects through irreversible cell cycle arrest in specific contexts. Therefore, a thorough investigation of GI’s dual role in aging and cancer can help reveal the shared biological basis of both processes and provide new strategies for the precise prevention and treatment of age-related tumors.

Aging tissues accumulate DNA damage, while genome instability is a defining feature of cancer. Despite this shared foundation, DNA damage is still largely viewed as a transient lesion that is either faithfully repaired or converted into a mutation. New evidence challenges this binary view, indicating that DNA double-strand breaks (DSBs), even when accurately repaired at the sequence level, can leave durable and heritable alterations in chromatin organization and gene regulation. Accordingly, DSB repair restores DNA integrity but does not necessarily re-establish the original regulatory architecture. The biological consequences of such post-repair regulatory memory remain largely underappreciated, progressively contributing to age-associated tissue dysfunction while simultaneously creating permissive states for malignant transformation and therapy resistance. In this commentary, we argue that reframing DNA damage as a source of heritable regulatory change, rather than solely as a mutational event, reshapes our understanding of aging trajectories and cancer risk.

Cellular senescence results in a stable growth arrest of cells that is elicited by endogenous or exogenous stresses. Senescent cells release a broad spectrum of proinflammatory factors, a collective signature known as the senescence-associated secretory phenotype. Senescence modulates tumor initiation and progression via a context-dependent dual role, acting as both a tumor suppressor and a promoter. Triggering cellular senescence restricts cancer progression and enhances therapy outcomes, however, the accumulation of senescent cells drives tumor progression, recurrence, and metastasis. Thus, selective targeting of senescent cells holds the potential to develop novel therapeutic approaches to combat cancer. In this review, we delineate the regulatory mechanisms controlling cellular senescence in tumors. We also summarize the emerging senescence-targeting agents and their utility in anticancer intervention. Given the complex role of senescent cells in cancer, a comprehensive understanding of these processes will create new opportunities for effective anticancer therapy.

Cytoplasmic chromatin fragments (CCFs) are structures formed by nuclear chromatin leaked into the cytoplasm in response to cellular senescence, stress, or tumorigenesis, primarily due to genomic instability and nuclear envelope rupture. These cytoplasmic DNA fragments are recognized by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and activate the cGAS–STING pathway, which promotes activation of IRF3 and NF-κB, and induces expression of type I interferons and pro-inflammatory cytokines, thereby driving the senescence-associated secretory phenotype (SASP). CCFs are not only a hallmark of cellular senescence but also a critical signaling hub that links DNA damage to chronic inflammation via SASP factors like IL-6 and IL-8, reinforcing senescence through autocrine and paracrine loops. In cancer, CCFs play distinct roles at different stages: in early-stage tumors, they induce cell cycle arrest and enhance immune surveillance, thereby suppressing tumor initiation; whereas in advanced tumors, persistent CCFs chronically activate the cGAS–STING–NF-κB signaling axis, promoting epithelial–mesenchymal transition, angiogenesis, metastasis, and immune evasion. Notably, CCFs formation is heterogeneous and regulated by key factors such as p53, 53BP1, and Lamin B1. Therefore, targeting the CCFs–cGAS–STING pathway and its upstream regulators, including mitochondrial function, autophagy, and epigenetic modifications, offers a promising strategy to alleviate aging-related diseases and improve cancer therapy by suppressing SASP and blocking tumor progression. This review summarizes the mechanisms of CCFs biogenesis, their complex roles in aging and cancer, and emerging therapeutic approaches aimed at this axis, offering insights for both basic research and clinical translation.

Transcription–replication conflicts (TRCs) are an increasingly recognized driver of genome instability in human cells. We recently identified the CUL3 adaptor KCTD10 as a sensor of co-directional TRCs, recruiting CUL3 to ubiquitinate transcriptional machinery and clear the path for replication forks. Here, we discuss the implications of this conflict-resolution pathway for human cancer. By integrating our mechanistic findings with large-scale functional genomics datasets, we identify oncogenic conditions that potentially create TRC-rich environments and render cells selectively dependent on KCTD10. These contexts reveal new mechanistic insights and potential therapeutic opportunities across a range of human cancers.

Sister chromatid cohesion, established during DNA replication, is essential for accurate chromosome segregation. While acetylation of the cohesin subunit SMC3 by ESCO1/2 promotes the recruitment of the cohesin stabilizer Sororin, this pathway is insufficient for full Sororin function. In a recent study, Jiang et al. identify a previously uncharacterized human microprotein, RSMC, as a Sororin cofactor required for sister chromatid cohesion. The authors show that RSMC interacts with Sororin, and this interaction is enhanced during S-phase by PARP1/2-mediated poly(ADP-ribosyl)ation (PARylation) of RSMC. PARylation of RSMC, triggered by DNA replication intermediates, acts in parallel with SMC3 acetylation to ensure the timely and efficient recruitment of Sororin to chromatin. Consequently, inhibition of PARP activity reduces chromatin-bound Sororin and causes cohesion defects, which can be rescued by overexpressing wild-type RSMC or Sororin, but not by PARylation- or interaction-deficient mutants. Furthermore, RSMC stimulates the anti-Wapl activity of Sororin in vitro, promoting stable cohesin binding. Taken together, the work of Jiang et al. describes a dual, replication-coupled regulatory mechanism wherein S-phase PARylation of the microprotein RSMC cooperates with SMC3 acetylation to fully enable Sororin’s function in establishing sister chromatid cohesion. This mechanism is important for maintaining genomic stability, and its dysregulation may contribute to chromosome segregation errors observed in cancer.