Frailty refers to a state of heightened vulnerability to adverse health outcomes. Animal models of frailty provide an opportunity to probe lifetime events and exposures that drive frailty progression and to evaluate intervention strategies that could mitigate frailty development and its consequences in older adults. The relationship between parity-production of live offspring-and later life frailty in women is poorly understood. Here, we utilize companion dogs to test the hypothesis that production of live offspring comes at a physiological cost, leading to increased late-life frailty. We measured deficit accumulation using a 34-item clinical frailty index in a cohort of 95 geriatric female Rottweilers. The study outcome was late-life robustness, defined as the lowest quintile of frailty in the study population. We found no evidence of reproductive cost. Instead, compared to nulliparous females, parous females were 3× more likely to retain late-life robustness [OR, 95% CI = 3.30,1.16-9.38; p = .025], a relationship not attenuated by adjusting for covariates, including owner-reported reason for nulliparity. Moreover, females with largest number of litters had highest late-life robustness. Finally, employing two measures of early-life health/fitness-earlier-in-life health deficits, lifetime morbidity profiles-could not explain results based on selection. This inquiry introduces a new application of the dog model of frailty for the study of reproduction and deficit accumulation. The linkage we observed between parity and higher late-life robustness is congruent with results of several studies in women, suggesting parous females may have the capacity to dampen the development of later-in-life frailty, which should be further investigated at the genetic and epigenetic level.
UHRF1 is a key epigenetic regulator implicated in the tumorigenesis of various cancers through DNA methylation; however, its specific mechanisms in the progression of lung adenocarcinoma (LUAD) remain poorly understood. This study aims to elucidate the regulatory role of UHRF1 in LUAD, focusing on its impact on cuproptosis. UHRF1 expression and its correlation with patient prognosis were analyzed using the TCGA-LUAD dataset. Expression levels of UHRF1 and FDX1 in LUAD cell lines were verified via qPCR and Western blot. Gene Set Enrichment Analysis (GSEA) was employed to explore UHRF1-associated pathways. The impact of UHRF1 on cuproptosis was assessed using CCK-8 assays, metabolite detection, and apoptosis analysis. Mechanistically, Chromatin Immunoprecipitation (ChIP) and Methylation-Specific PCR (MSP) were performed to investigate the binding and methylation status of the FDX1 promoter. Finally, the oncogenic role of UHRF1 was validated in vivo using a xenograft mouse model. Clinical analysis revealed that elevated UHRF1 expression in LUAD tissues is significantly associated with poor prognosis. At the cellular level, UHRF1 overexpression downregulated FDX1 expression and inhibited DLAT oligomerization. Functional enrichment analysis indicated that UHRF1 is involved in metabolic reprogramming; specifically, its overexpression enhanced glycolysis while suppressing cuproptosis. Mechanistic studies demonstrated that UHRF1 binds directly to the FDX1 promoter, inducing hypermethylation and subsequent transcriptional silencing. Rescue experiments confirmed that restoring FDX1 expression reverses the cuproptosis-suppressive effects of UHRF1. In vivo, UHRF1 knockdown retarded tumor growth and promoted cell death, whereas concurrent FDX1 knockdown attenuated these tumor-suppressive effects. UHRF1 negatively regulates FDX1 expression through DNA methylation, thereby inhibiting cuproptosis and driving LUAD progression. These findings clarify a novel epigenetic mechanism underlying LUAD and highlight the UHRF1/FDX1 axis as a potential therapeutic target.
It is proposed that the origin of temperament is rooted in events of the third week of gestation, when gastrulation and the notochord organize body axes and morphogenetic gradients, integrated through intracellular pathways with downstream effects on circuit architecture and locomotion. To propose a theoretical mechanistic model that articulates how gastrulation, the notochord, and prenatal epigenetic programming could contribute-probabilistically rather than deterministically-to the origin of human temperament. Original contribution of opinion/theoretical model, derived from an interdisciplinary narrative review. No experiments or quantitative meta-analyses were conducted; the aim is to articulate a hypothesis-generating mechanistic framework. A three-phase mechanistic flow is proposed: Phase 1, in which gastrulation and the notochord establish axes and gradients that could modulate the organization of ventral circuits and central pattern generators; Phase 2, in which prenatal epigenetic programming calibrates stress, immune, and affective axes; and Phase 3, in which these levels integrate into profiles of activity, exploration, reactivity, and inhibition, consistent with the distributed polygenic architecture described by personality genomics. The notochord emerges as a plausible morphogenetic axis of temperament. Upon this embryonic scaffold, prenatal epigenetic programming may calibrate allostasis, stress reactivity, and affectivity, contributing to long-term temperamental variation. The model formulates falsifiable hypotheses and suggests translational priorities in perinatal prevention, multimodal biomarkers, and personalized neurodevelopmental medicine, whose short-term clinical feasibility remains uncertain. se propone que el origen del temperamento se ancla en eventos de la tercera semana de gestación, cuando la gastrulación y la notocorda organizan ejes corporales y gradientes morfogenéticos, integrados por vías intracelulares con efectos descendentes sobre la arquitectura de circuitos y la locomoción. proponer un modelo mecanístico teórico que articule cómo la gastrulación, la notocorda y la programación epigenética prenatal podrían contribuir, de manera probabilística y no determinista, al origen del temperamento humano. aportación original de opinión/modelo teórico, derivada de una revisión narrativa interdisciplinaria. No se realizaron experimentos ni metaanálisis cuantitativos; el objetivo es articular un marco mecanístico generador de hipótesis. se articula un flujo mecanístico en tres fases: Fase 1, en la que la gastrulación y la notocorda fijan ejes y gradientes que podrían modular la organización de circuitos ventrales y generadores centrales de patrones; Fase 2, en la que la programación epigenética prenatal calibra ejes de estrés, inmunidad y afectividad, y Fase 3, en la que estos niveles se integran en perfiles de actividad, exploración, reactividad e inhibición compatibles con la arquitectura poligénica distribuida descrita por la genómica de la personalidad. la notocorda emerge como un eje morfogenético plausible del temperamento. Sobre este andamiaje embrionario, la programación epigenética prenatal podría calibrar la alostasis, la reactividad al estrés y la afectividad, contribuyendo a la variación temperamental a largo plazo. El modelo formula hipótesis falsables y sugiere prioridades traslacionales en prevención perinatal, biomarcadores multimodales y medicina personalizada del neurodesarrollo, cuya viabilidad clínica a corto plazo sigue siendo incierta.
ATP-citrate lyase (ACLY) is a key metabolic enzyme that links mitochondrial citrate export to the generation of cytosolic acetyl-CoA, thereby supporting de novo lipogenesis, cholesterol biosynthesis, protein acetylation, chromatin remodelling, and transcriptional control. Interest in ACLY inhibition initially arose from its lipid-lowering properties and led to the clinical development of bempedoic acid, whose ability to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes now provides the strongest clinical proof of concept for targeting this pathway. Beyond dyslipidaemia, preclinical evidence suggests that targeting the ACLY pathway and related bempedoic acid-responsive metabolic programs may ameliorate metabolic dysfunction-associated steatotic liver disease (MASLD). ACLY inhibition is expected to reduce de novo fatty-acid and cholesterol synthesis by limiting cytosolic acetyl-CoA availability, whereas parent bempedoic acid can directly activate PPARα, and thereby enhance fatty-acid oxidation. However, unlike the cardiovascular setting, robust clinical data supporting ACLY inhibition in MASLD are still lacking. More recently, the identification of nuclear ACLY functions has substantially expanded its biological significance, establishing ACLY as a metabolic-epigenetic integrator that couples nutrient availability to chromatin remodelling, transcriptional programs and immune responses. In cancer, dysregulated ACLY activity contributes to tumour growth, metabolic plasticity, therapy resistance and immune evasion, and its inhibition has shown promising antitumour effects in preclinical models. This review summarizes ACLY biology and pharmacology, emphasizing established cardiovascular applications, emerging MASLD opportunities and exploratory oncologic indications, while highlighting unresolved translational questions.
Cytoskeleton is an important component of cell structure and function. In the cardiovascular system, it is involved in the remodeling process of a variety of cardiovascular diseases, including cardiac fibrosis, valvular disease, atrial fibrillation, thoracic aortic aneurysm and vascular stiffness related changes. Recent studies have shown that there is a significant synergy between cytoskeletal regulation and epigenetic processes. Notably, epigenetic alterations have been identified as one of the core features of ageing, a major risk factor for cardiovascular disease. Together, these factors regulate the fate determination, function maintenance and pathological transformation of cardiovascular cells. This review focuses on how age-related epigenetic changes, such as DNA methylation, histone modifications, and chromatin remodeling, directly affect cytoskeletal dynamics and nuclear mechanics, and ultimately lead to cardiovascular remodeling. This review systematically summarizes the key molecular pathways that drive pathological remodeling of cardiomyocytes during contraction, phenotypic switching of vascular smooth muscle cells, and activation of fibroblasts. In addition, we discuss potential therapeutic targets, biomarkers, and intervention strategies in this rapidly evolving field to address current challenges and identify future directions for research in order to lay the theoretical foundation for precision medicine in cardiovascular disease.
Hypertension is a major risk factor for cardiovascular disease and alters the mechanical microenvironment of the vascular wall and target organs. Key mechanical disturbances include disturbed shear stress, excessive circumferential stretch, elevated hydrostatic pressure, and increased extracellular matrix stiffness. These forces are sensed by multiple classes of mechanosensors, including mechanosensitive ion channels, integrin-based adhesion complexes, G protein-coupled receptors, primary cilia, baroreceptor afferents, and nuclear mechanosensing structures. Activation of these sensors engages interconnected Ca²⁺-dependent, RhoA/Rho-associated protein kinase, mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, redox-sensitive, inflammatory, and mechano-epigenetic pathways. This review summarizes how altered mechanotransduction may contribute to endothelial dysfunction, vascular smooth muscle cell phenotypic switching, vascular remodeling, and cardiac and renal target-organ injury in hypertension. Mechanotransduction is unlikely to represent a universal initiating cause of hypertension. Rather, it should be viewed as a context-dependent set of adaptive and maladaptive responses that varies according to cell type, vascular bed, mechanical stimulus, disease stage, and experimental model. Physiological mechanotransduction helps maintain vascular homeostasis and baroreflex function, whereas sustained pathological loading may amplify oxidative stress, inflammation, fibrosis, and vascular stiffening. However, most direct mechanistic evidence derives from cultured cells and animal models, and human genetic, tissue, biomarker, and interventional data remain limited. Conventional antihypertensive therapy therefore remains the foundation of clinical management, whereas direct targeting of mechanosensors or downstream mechanotransduction pathways remains experimental and requires stronger human validation.
Acidic nuclear phosphoprotein 32A (ANP32A) is not only a core component of the inhibitor of histone acetyltransferases (INHAT) complex but also a crucial pleiotropic protein regulating cellular homeostasis and disease progression. Its extensive involvement in transcriptional regulation, apoptotic cascades, and signal transduction underpins its pivotal role across virology, neurobiology, and oncology. This review systematically elucidates the structure-function relationship of ANP32A, delineating its role as an essential host factor for viral replication​ and its complex involvement in neurodegenerative processes. Particular emphasis is placed on its context-dependent duality within oncology, where it exerts a pronounced "double-edged sword" effect by acting as either a tumor suppressor or an oncogene depending on the cellular milieu. Ultimately, this article aims to provide a theoretical foundation for the development of precision-targeted clinical interventions directed at ANP32A.
This narrative review synthesizes current evidence on oral aging in older adults across three clinically relevant domains: mechanisms, assessment and clinical relevance for gerodontology. Older adults experience a disproportionate burden of oral disease, tooth loss, oral hypofunction and oral frailty. These conditions are often managed as isolated dental problems despite their interconnections with function, nutrition, quality of life and broader geriatric vulnerability. This narrative review synthesizes current evidence on oral aging in older adults across three clinically relevant domains: biological mechanisms, assessment approaches and relevance to gerodontological care. Oral aging reflects interactions among oral dysbiosis, chronic periodontal inflammation, immune dysregulation, cellular senescence, impaired tissue repair and declining oral function. Emerging assessment approaches include salivary biomarkers, oral functional phenotyping, epigenetic clocks and multimodal computational methods; current evidence supports interpreting these measures as tissue-specific and complementary, rather than as direct substitutes for systemic measures. Relevant clinical strategies include periodontal care, prosthetic rehabilitation, oral functional exercise and integrated multidisciplinary care. Oral aging is a multidimensional construct linking biological change, functional decline and geriatric vulnerability. Future progress requires stronger validation of assessment tools, clinically meaningful functional endpoints and greater integration of oral health within aging care.
Cervical cancer (CC) remains a leading malignancy among women worldwide. Epigenetic and transcriptional dysregulation complicate the identification of causal genes with prognostic and therapeutic relevance. We performed a multi-omics integrative analysis combining summary data-based Mendelian randomization (SMR) using eQTL and pQTL datasets with genome-wide association study (GWAS) summary statistics (ID: ukb-b-8777) to prioritize candidate genes associated with CC. Differential expression analyses were conducted using multiple GEO cohorts, and protein expression was validated by immunohistochemistry (IHC) in clinical specimens. DNA methylation profiling and correlation analyses were performed using GEO and TCGA datasets to investigate epigenetic regulation. Kaplan-Meier and combined expression-methylation survival analyses were used to evaluate prognostic significance. Functional validation was conducted in HeLa cells using wound-healing and CCK-8 assays following FAM3D knockdown or overexpression. RNA sequencing was further performed to explore the downstream molecular pathways regulated by FAM3D. Integrative SMR analysis identified FAM3D as a protective gene for CC. FAM3D expression was significantly reduced in CC tissues and exhibited a progressive decline from normal cervical tissues to cervical intraepithelial neoplasia (CIN) and invasive CC, which was further confirmed by IHC. Promoter hypermethylation of FAM3D (cg26334888) was associated with its transcriptional downregulation and negatively correlated with gene expression. Survival analyses demonstrated that high FAM3D expression (p = 0.016) and low promoter methylation (p = 0.048) were associated with favorable overall survival, while combined expression-methylation analysis further improved prognostic stratification (p = 0.006). Functional assays showed that FAM3D suppressed CC cell proliferation and migration. Transcriptomic profiling revealed that FAM3D restoration induced extensive transcriptional reprogramming and was associated with inflammatory signaling, cytokine-mediated pathways, and extracellular matrix remodeling. Key hub genes identified downstream of FAM3D included CXCL8, MMP1, EREG, and LCN2. FAM3D is a potential tumor suppressor and prognostic biomarker in CC, whose expression is partially regulated by promoter methylation. Integrative multi-omics analyses and functional studies suggest that FAM3D may inhibit CC progression through modulation of inflammatory signaling and extracellular matrix-associated pathways. These findings provide new insights into the molecular mechanisms underlying CC and support the potential clinical utility of FAM3D as a prognostic biomarker and therapeutic target.
Breast cancer encompasses molecularly distinct subtypes with divergent oncogenic dependencies, each amenable to precision therapeutic intervention. Over the past decade, clinically meaningful advances have reshaped breast cancer management: antibody-drug conjugates (ADCs) have expanded actionable HER2 expression thresholds to include HER2-low and HER2-ultralow populations; cyclin-dependent kinase (CDK) 4/6 inhibitors have become standard-of-care in hormone receptor-positive disease; and immune checkpoint blockade has established durable responses in a defined subset of triple-negative breast cancer (TNBC). Nevertheless, therapeutic resistance remains the central unresolved obstacle to durable benefit. Here, we synthesize current evidence on the signaling architecture underlying targeted therapy across breast cancer subtypes and propose a four-layer network topology model of resistance integrating: (i) canonical pathway reactivation; (ii) receptor tyrosine kinase (RTK) reprogramming; (iii) non-coding RNA (ncRNA) regulatory circuits; and (iv) epigenetic plasticity coupled with tumor microenvironment (TME) co-evolution. We explicitly stratify the discussed mechanisms into three evidence tiers-clinically actionable, plausibly translational, and exploratory-to avoid conflating preclinical observations with validated biomarkers. We critically evaluate FDA-approved and emerging agents within this framework, identify knowledge gaps, and outline future directions-including liquid biopsy-guided adaptive therapy, multi-omic resistance profiling, and biologically rational combination strategies-together with their feasibility constraints related to toxicity, sequencing, cost, and biomarker validation.
Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are abundant viral noncoding RNAs that associate with host chromatin, but the promoter-scale consequences of those contacts remain unclear. We re-analyzed GSE281522 in EBV-positive GM12878 cells integrating RNA-DNA contacts, RNAPII ChIA-PET, RNA-seq and internal ATAC-seq after EBER depletion. Promoters were classified according to increased RNAPII-associated promoter-looping signal after EBER depletion relative to the matched control conditions, defined as LoopRecovery; increased transcriptional output, defined as ExprUp; or the coordinated occurrence of both responses, defined as Recovery + Up. EBER-contacted promoters were markedly depleted for Recovery + Up relative to non-contacted promoters (0.42% vs 2.00%; OR ~ 0.21; Fisher's exact p ~ 6.3 × 10-5), and the association between increased promoter looping and transcriptional upregulation was attenuated among EBER-contacted promoters. This depletion remained directionally stable across alternative threshold grids, loop-support and expression filters, and promoter-window definitions using TSS-centered intervals of ± 1 kb, ± 2 kb and ± 5 kb (ORs 0.416, 0.208 and 0.110, respectively). To test whether the constrained class simply reflected inactive chromatin, we integrated internal ATAC-seq from the same study. Constraint-core promoters, defined as EBER-contacted promoters that did not enter Recovery + Up, remained accessible, with ATAC overlap observed in 89.38% versus 68.38% of comparator promoters in any replicate and higher replicate-averaged ATAC signal (median 42.55 vs. 10.43). Ranked Hallmark enrichment and top-contact over-representation converged on TNFA_SIGNALING_VIA_NFKB as the strongest pathway-level signal, and candidate loci including RIPK2, IL15RA, ICAM1, TNFAIP3 and NFKBIA defined accessible but constrained promoter hubs. Control RNA contact maps did not reproduce a uniform EBER-like phenotype. Together, these analyses support a model in which EBER-associated contacts mark accessible yet transcriptionally constrained RNAPII promoter hubs in EBV-positive B cells.
Neighborhood socioeconomic disadvantage is linked to accelerated biological aging using DNA methylation; however, limited knowledge exists of the relationship between duration or timing of exposure to neighborhood poverty across life stages and biological aging, measured by epigenetic clocks. Existing research has relied on samples with limited racial and gender diversity. We examined the relationship between multiple dimensions of neighborhood poverty (duration, life stage of first exposure, life stage exposure trajectories, and severity) and biological aging using data from 3637 participants followed for 25 years in the National Longitudinal Study of Adolescent to Adult Health. We employed survey linear regression models to estimate associations for three epigenetic clocks: GrimAge2, PhenoAge, DunedinPACE. In the total sample, only 8% of participants experienced neighborhood poverty across all life stages, which differed starkly by race (Non-Hispanic Blacks: 26% vs. Non-Hispanic Whites: 4%). We found that each additional life stage of exposure to neighborhood poverty was associated with significant biological age acceleration. Experiencing neighborhood poverty in mid-adulthood was consistently associated with accelerated biological aging. Our results suggest a relationship between duration and timing of exposure to neighborhood poverty and accelerated biological aging across key biological clocks, indicating possible lasting cellular level effects of residential context.
During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver-brain, liver-muscle, and liver-gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.
Esophageal cancer is a type of malignant tumor with high incidence and mortality rates worldwide, and esophageal squamous cell carcinoma (ESCC) is the predominant pathological subtype in China. Despite continuous advancements in treatment methods, the prognosis of ESCC patients remains poor and there is an urgent need to develop new therapeutic strategies. Recent epigenetic frontiers have identified the dysregulation of lysine acetylation, a dynamic and reversible post-translational modification, as a pivotal driver of ESCC pathogenesis. This process is orchestrated by a dynamic interplay between "writers" (lysine acetyltransferases, KATs), "erasers" (lysine deacetylases, KDACs), and "readers". In this review, we systematically delineate the molecular landscape of lysine acetylation in ESCC and emphasize how these epigenetic modulators reshape the transcriptional program of tumor cells. Specifically, we highlight the oncogenic or tumor-suppressive roles of key acetylating enzymes and their non-histone substrates, which bridge the gap between epigenetic alterations and malignant phenotype. And we summarize the latest research progress and clinical application potential of KAT inhibitors (KATi), KDAC inhibitors (KDACi), and inhibitors of lysine acetylation readers in various tumor. Additionally, we discuss the challenges of drug resistance in epigenetic therapy and opportunities in targeting acetylation modification. By providing a comprehensive synthesis of the acetylation-ESCC axis, this review aims to offer theoretical guidance for the development of novel epigenetic biomarkers and targeted interventions to improve the prognosis of ESCC patients.
Organisms adapt to novel environments using changes to genome, gene expression, and protein functions. This study focused on changes that had occurred when a fungal pathogen previously encountered hosts that differed only at the major histocompatibility complex (MHC) region, loci that control immune recognition during the adaptive immune response. To investigate how this fungal pathogen adapted to the host environment, next generation sequencing data were examined from strains of Cryptococcus neoformans (C. neoformans) that had been previously passaged eight times through congenic mice that specifically differed at the MHC locus, H2. Transcript levels and the genomic sequence for each post-adapted fungal strain were examined to identify molecular adaptation strategies via heritable gene expression changes (epigenetic changes) and mutation (DNA changes). The post-adapted strains displayed repeated changes in transcript levels, as determined by RNA-sequencing. Some of these epigenetically regulated genes (ERGs) only occurred in strains passaged in MHC specific hosts, suggesting possible prior adaptations to specific host MHCs. To our knowledge, this is the first time ERGs have been reported as possible pathogen adaptations to specific host MHC alleles. Additionally, of the total 47 single nucleotide polymorphisms (SNPs) identified, 7 SNPs each were found in 2 or more fungal strains (of the 6 analyzed strains) passaged through different MHC congenic hosts, suggesting much of the fungal mutation-based adaptation was to the mouse host, and not MHC-specific. These data demonstrated that these passaged C. neoformans strains adapted to the MHC haplotype of a novel mammalian host environment primarily via epigenetic rather than mutation-based mechanisms.
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RNA interference (RNAi) in nematodes is amplified through the generation of secondary small interferring RNA (siRNA) from products of primary siRNA cleavage. This process requires RDE-3, a unique ribonucleotidyltransferase that adds a poly(UG) tail of alternating U and G nucleotides without a template. Here we demonstrated using in vitro enzymatic assays that RDE-3 is intrinsically specific for substrate combinations that correctly extend the pUG tail and optimized for effective pUGylation in vivo. Specificity for cognate substrate pairs (3'-G RNA with UTP or 3'-U RNA with GTP) was driven primarily by a faster turnover rate, whereas non-cognate GG or UU extensions were dramatically slower. RDE-3 could also extend 3'-A or 3'-C RNA substrates with GTP or UTP, allowing it to initiate pUGylation of primary RNAi products, but at slower rates and with little GTP/UTP preference. We established an assay where products of both 3'-G and 3'-U RNA substrates in a reaction with GTP and UTP were followed simultaneously. We found that pUG extension was optimal and most accurate under conditions where GTP/UTP concentrations corresponded to their relative KMNTP values and typical cellular conditions.
The synergistic crosstalk between epigenetic dysregulation and metabolic reprogramming underlies to prostate cancer (PCa) development and treatment resistance, yet an integrated prognostic signature reflecting this nexus remains poorly defined. We developed and validated a gene signature associated with methylation and amino acid metabolism for patient stratification and exploring its connection to tumor microenvironment (TME) remodeling. RNA sequencing data and independent datasets were integrated with predefined gene sets for DNA methylation (n = 79) and amino acid metabolism (n = 471). A analytical workflow was employed: identification of hub genes and least absolute shrinkage and selection operator (LASSO)-Cox modeling; construction of a prognostic nomogram; comprehensive TME profiling; and validation through single-cell RNA sequencing (scRNA-seq) cellular dynamics analysis and immunohistochemistry (IHC) on a prostate cancer tissue microarray. A novel six-gene prognostic model (ASPM, WDR86, CCK, HOXA2, EGF, ZFHX4) was developed. This model efficiently discriminates patients into groups based on risk level though divergent overall survival (p < 0.001) and exhibited high predictive accuracy in external validation sets (3-year area under the curve (AUC) = 0.87). A nomogram incorporating the signature, pathologic T stage, and Gleason score surpassed individual clinical factors (5-year AUC = 0.73). Functional annotation indicated that high-risk tumors were characterized by downregulated androgen response and activated E2F/G2M checkpoint pathways. The signature was correlated with an immunosuppressive TME, which was supported by a negative correlation between ZFHX4 and monocyte infiltration (r = -0.37, p < 0.001) and a positive correlation between ASPM and activated CD4+T cells (r = 0.44, p < 0.001). Single-cell trajectory analysis exhibited that epithelial cells, fibroblasts, and natural killer T (NKT) cells was key cellular expressors of the signature. We utilized immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) to confirm the differential expression. We developed and validated an integrative methylation-amino acid metabolism gene signature that effectively predicts prognosis and reflects an immunosuppressive TME in PCa. This study provides a translational framework for precision oncology, bridging epigenetic-metabolic crosstalk to disease aggressiveness, and offers potential biomarkers for informing risk-stratified therapy and immunotherapy approaches.
Ependymoma-like tumor with mesenchymal differentiation (ELTMD) is a recently proposed, but not yet formally defined, entity that is not recognized in the 2021 World Health Organization (WHO) classification of central nervous system tumors. Although it shares molecular features, such as ZFTA fusion, with ependymomas, it exhibits distinct histopathological and epigenetic profiles. Herein, we report the case of a 5-year-old girl with a supratentorial tumor harboring the ZFTA::NCOA2 fusion. Histopathology revealed atypical features including mesenchymal and undifferentiated components, which overlapped with those of ependymomas. DNA methylation profiling using two independent classifiers (DKFZ and NIH) yielded no matches, indicating that the tumor did not belong to any recognized CNS class. The failure of subclass assignment by both classifiers suggests that ELTMD represents a potentially epigenetically distinct subgroup. Despite being unclassifiable by the current WHO criteria, the tumor shared features with previously reported ELTMDs, supporting its recognition as an emerging tumor. This highlights the need for additional cases to refine the diagnosis, classification, and future therapeutic strategies.
Endometriosis (EMs) is a common gynecological disorder affecting reproductive‑aged women, characterized by ectopic endometrial growth and chronic pelvic pain that severely impairs quality of life. Although its pathogenesis remains incompletely understood, accumulating evidence indicates that the tumor suppressor p53 and aberrant epigenetic modifications play critical roles in EMs initiation and progression. p53 expression is significantly reduced in ectopic lesions, leading to apoptosis resistance and hyperproliferation of endometrial cells. Importantly, p53 dysfunction contributes to EMs through at least four epigenetic mechanisms: (1) p53 transcriptionally represses DNA methyltransferases (DNMTs), and its loss indirectly promotes locus‑specific hypermethylation and silencing of tumor suppressors; (2) p53, via its interaction with histone modifiers, influences their recruitment to target genes, and p53 impairment synergizes with histone deacetylase dysregulation to create a pro‑proliferative, anti‑apoptotic microenvironment; (3) p53 functionally interacts with the chromatin remodeler ARID1A, and their co‑dysruption impairs chromatin accessibility and immune homeostasis; (4) p53 coordinates non‑coding RNA networks (e.g. lncRNA MALAT1, miR‑34a) that regulate epithelial-mesenchymal transition, angiogenesis, and apoptosis. This review systematically summarizes the p53‑mediated epigenetic regulatory network in EMs and highlights potential therapeutic opportunities targeting p53-epigenetic crosstalk. Future studies should investigate synergistic mechanisms among different epigenetic layers and validate these findings in multi‑center clinical cohorts.