Search Results (969)

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Background/Objectives: Different risk factors are involved in the initiation and progression of melanoma. In particular, genetic and epigenetic pathways are involved in all stages of melanoma and are exploited in therapeutic approaches. This study investigated the role of circular RNA circ_0001591 in melanoma cell migration. Methods: Three different melanoma cell lines were transfected with siRNA targeting circ_0001591 and with mimic or inhibitor molecules for miR-20a-3p and miR-34a-5p. Gene and protein expression levels were analyzed by RT-qPCR and Western blot, respectively. Dual luciferase reporter assays were performed to confirm the direct interaction of miR-20a-3p and miR-34a-5p with circ_0001591, as well as with the 3’UTRs of AXL (for both miRNAs) and FOSL1 (miR-34a-5p only). Wound healing assays were conducted to assess cell migration velocity. Results: The silencing of circ_0001591 significantly reduces the migration ability of melanoma cell lines. This downregulation was associated with an increased expression of miR-20a-3p and miR-34a-5p. Dual luciferase reporter assays confirmed the direct binding of both miRNAs to circ_0001591, supporting its role as a molecular sponge. The same assays also verified that miR-20a-3p directly targets the 3’UTR of AXL, while miR-34a-5p binds the 3’UTRs of both AXL and FOSL1. Western blot analysis showed that the modulation of this axis affects the expression levels of the AXL and FRA1 oncoproteins. Conclusions: Our findings demonstrate that circ_0001591 promotes melanoma migration by sponging miR-20a-3p and miR-34a-5p, thereby indirectly modulating the expression of AXL and FRA1 oncoprotein. Further investigations of this new regulatory network are needed to better understand its role in melanoma progression and to support the development of targeted therapies. Full article

Background/Objectives: Krüppel-like factor 4 (KLF4) emerged as an epigenetically regulated gene in a variety of settings, including cell reprogramming and malignant cell proliferation. The aim of the present manuscript is to explore the relationship described in recent years between circular RNAs, miRNAs, and KLF4. These have been shown to be involved in cancers having diverse histological origins, including some of the most prevalent and deadly tumors for the human population. Expression and protein levels of this transcription factor correlate with invasiveness and prognosis in a context- and tissue-specific fashion. Methods: The literature was obtained through two main PubMed queries. The first is “miRNA and KLF4 and cancer” and is limited to the last 5 years. The second is “circRNA and KLF4”, which yielded publications between 2013 and 2024. The oncological publications were selected. Results: A number of circRNA/miRNA axes that regulate the downstream transcription factor KLF4 emerged in the last few years. circRNAs act as sponges for miRNAs and synergize with KLF4, which can function as either a tumor promoter or suppressor in different tumors. Conclusions: The axes represented by circRNA/miRNA/KLF4 emerged as a new layer of epigenetic regulation. These RNA-based modulators explain the complex regulation of this transcription factor and open the way to new therapeutic targeting possibilities. Full article

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that continue to raise concern owing to their ability to accumulate in living organisms. In recent years, a growing body of research has shown that PFAS can exert their toxicity through disruption of both DNA integrity and epigenetic regulation. This includes changes in DNA methylation patterns, histone modifications, chromatin remodeling, and interference with DNA repair mechanisms. These molecular-level alterations can impair transcriptional regulation and cellular homeostasis, contributing to genomic instability and long-term biological dysfunction. In neural systems, PFAS exposure appears particularly concerning. It affects key regulators of neurodevelopment, such as BDNF, synaptic plasticity genes, and inflammatory mediators. Importantly, epigenetic dysregulation extends to non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which mediate post-transcriptional silencing and chromatin remodeling. Although direct evidence of transgenerational neurotoxicity is still emerging, animal studies provide compelling hints. Persistent changes in germline epigenetic profiles and transcriptomic alterations suggest that developmental reprogramming might be heritable by future generations. Additionally, PFAS modulate nuclear receptor signaling (e.g., PPARγ), further linking environmental cues to chromatin-level gene regulation. Altogether, these findings underscore a mechanistic framework in which PFAS disrupt neural development and cognitive function via conserved epigenetic and genotoxic mechanisms. Understanding how these upstream alterations affect long-term neurodevelopmental and neurobehavioral outcomes is critical for improving risk assessment and guiding future interventions. This review underscores the need for integrative research on PFAS-induced chromatin disruptions, particularly across developmental stages, and their potential to impact future generations. Full article

Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS. Full article

Wharton’s jelly mesenchymal stem cells (WJ-SCs) are a promising source for regenerative medicine due to their multipotency, low immunogenicity, and ethical acceptability. Epigenetic regulation plays a crucial role in modulating their proliferation, differentiation, and therapeutic potential. Key mechanisms, including DNA methylation, histone modifications, and non-coding RNAs (e.g., miRNAs and lncRNAs), influence WJ-SC behavior by dynamically altering gene expression without changing the DNA sequence. DNA methylation often silences genes involved in differentiation, while histone acetylation/methylation can activate or repress lineage-specific pathways. Non-coding RNAs further fine-tune these processes by post-transcriptional regulation. Understanding these mechanisms could optimize WJ-SC-based therapies for tissue repair and immune modulation. This review summarizes current insights into epigenetic regulation in WJ-SCs and its implications for regenerative applications. Full article

Prenatal and postnatal skeletal muscle development in ruminants is coordinated by interactions between genetic, nutritional, epigenetic, and endocrine factors. This review focuses on the influence of maternal nutrition during gestation on fetal myogenesis, satellite cell dynamics, and myogenic regulatory factors expression, including MYF5, MYOD1, and MYOG. Studies in sheep and cattle indicate that nutrient restriction or overnutrition alters muscle fiber number, the cross-sectional area, and the transcriptional regulation of myogenic genes in offspring. Postnatally, muscle hypertrophy is primarily mediated by satellite cells, which are activated via PAX7, MYOD, and MYF5, and regulated through mechanisms such as CARM1-induced chromatin remodeling and miR-31-mediated mRNA expression. Hormonal signaling via the GH–IGF1 axis and thyroid hormones further modulate satellite cell proliferation and protein accretion. Genetic variants, such as myostatin mutations in Texel sheep and Belgian Blue cattle, enhance muscle mass but may compromise reproductive efficiency. Nutritional interventions, including the plane of nutrition, supplementation strategies, and environmental stressors such as heat and stocking density, significantly influence muscle fiber composition and carcass traits. This review provides a comprehensive overview of skeletal muscle programming in ruminants, tracing the developmental trajectory from progenitor cell differentiation to postnatal growth and maturation. These insights underscore the need for integrated approaches combining maternal diet optimization, molecular breeding, and precision livestock management to enhance muscle growth, meat quality, and production sustainability in ruminant systems. Full article

Background: Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), are increasingly recognized as conditions arising from multifaceted interactions among genetic predisposition, environmental exposures, and epigenetic modifications. Among epigenetic mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and PIWI-interacting RNAs (piRNAs), have gained attention as pivotal regulators of gene expression during neurodevelopment. These RNA species do not encode proteins but modulate gene expression at transcriptional and post-transcriptional levels, thereby influencing neuronal differentiation, synaptogenesis, and plasticity. Objectives: This systematic review critically examines and synthesizes the most recent findings, particularly in the post-COVID transcriptomic research era, regarding the role of ncRNAs in the pathogenesis, diagnosis, and potential treatment of neurodevelopmental disorders. Methods: A comprehensive literature search was conducted to identify studies reporting on the expression profiles, functional implications, and clinical relevance of ncRNAs in neurodevelopmental disorders, across both human and animal models. Results: Here, we highlight that multiple classes of ncRNAs are differentially expressed in individuals with ASD and ADHD. Notably, specific miRNAs and lncRNAs demonstrate potential as diagnostic biomarkers with high sensitivity and specificity. Functional studies further reveal that ncRNAs actively contribute to pathogenic mechanisms by modulating neuronal gene networks. Conclusions: Emerging experimental data indicate that the exogenous administration of certain ncRNAs may reverse molecular and behavioral phenotypes, supporting their therapeutic promise. These findings broaden our understanding of neurodevelopmental regulation and open new avenues for personalized diagnostics and targeted interventions in clinical neuropsychiatry. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease associated with high morbidity and mortality. Both pulmonary and extrapulmonary comorbidities significantly influence disease progression and patient outcomes. Despite current therapeutic options, effective treatments remain limited. Quercetin, a naturally occurring flavonoid, has emerged as a promising compound due to its antioxidant, anti-inflammatory, and antifibrotic properties. Preclinical and clinical studies have demonstrated its ability to modulate key molecular pathways involved in IPF, including Nrf2, SIRT1/AMPK, and the regulation of fibrosis-associated microRNAs (miRNAs). Furthermore, quercetin shows therapeutic potential across a range of IPF-related comorbidities, including chronic obstructive pulmonary disease, pulmonary hypertension, lung cancer, cardiovascular disease, diabetes, and psychiatric disorders. Under these conditions, quercetin acts via epigenetic modulation of miRNAs and regulation of oxidative stress and inflammatory signaling pathways. This review highlights the multifunctional role of quercetin in IPF and its comorbidities, emphasizing its gene regulatory mechanisms and potential as an adjunctive or alternative therapeutic strategy. Full article

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting. Full article

Migraine is a neurovascular paroxysmal disorder characterized by neurogenic inflammation and has a remarkable impact on the quality of life. The Food and Drug Administration (FDA) approved onabotulinumtoxin A in 2010 for the prophylactic treatment of chronic migraine. Today, in its 4th decade, it is approved in 100 countries for 15 main indications. Its mechanism of action, based on the inhibition of neurotransmitter release from primary sensory neurons, is very complex: it affords antinociception, but it also has an analgesic effect on neuropathic pain conditions and reduces the need for rescue medications. Genetic variants have been investigated for their potential role in the pathogenesis and clinical expression of migraine and of the response to treatments. These studies primarily involved genes associated with vascular regulation and cardiovascular pathology, including those encoding angiotensin-converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR). However, epigenetics and, particularly, genetic and epigenetic modifications are still poorly studied in terms of understanding the mechanisms implicated in susceptibility to migraine, aura, chronification and response to symptomatic and preventive treatments. In particular, the aim of the present study is to gather evidence on the genetic variants and epigenetic modifications affecting the pathway of the calcitonin gene-related peptide (CGRP), the target of onabotulinumtoxin A and of all the novel monoclonal antibodies. Full article

Background and Objectives: VPS26A, a core component of the retromer complex, is pivotal to endosomal trafficking and membrane protein recycling. However, its expression profile, prognostic significance, and clinical relevance in liver hepatocellular carcinoma (LIHC) remain unexplored. This study investigates the prognostic potential of VPS26A by extensively analyzing publicly available LIHC-related databases. Materials and Methods: Multiple databases, including TIMER, UALCAN, HPA, GSCA, KM Plotter, OSlihc, MethSurv, miRNet, OncomiR, LinkedOmics, GeneMANIA, and STRING, were used to evaluate VPS26A expression patterns, prognostic implications, correlations with tumor-infiltrating immune cells (TIICs), epigenetic modifications, drug sensitivity, co-expression networks, and protein–protein interactions in LIHC. Results: VPS26A was significantly overexpressed at both the mRNA and protein levels in LIHC tissues compared to that in normal tissues. This upregulation was strongly associated with a poor prognosis. Furthermore, VPS26A expression was both positively and negatively correlated with various TIICs. Epigenetic analysis indicated that VPS26A is regulated by promoter and regional DNA methylation. Additionally, VPS26A influences the sensitivity of LIHC cells to a broad range of anticancer agents. Functional enrichment and co-expression analyses revealed that VPS26A serves as a central regulator of the LIHC transcriptomic landscape, with positively correlated gene sets linked to poor prognosis. Additionally, VPS26A contributes to the molecular architecture governing vesicular trafficking, with potential relevance to diseases involving defects in endosomal transport and autophagy. Notably, miRNAs targeting VPS26A-associated gene networks have emerged as potential prognostic biomarkers for LIHC. VPS26A was found to be integrated into a highly interconnected signaling network comprising proteins in cancer progression, immune regulation, and cellular metabolism. Conclusions: Overall, VPS26A may serve as a potential prognostic biomarker and therapeutic target in LIHC. This study provides novel insights into the molecular mechanisms underlying LIHC progression, and highlights the multifaceted role of VPS26A in tumor biology. Full article

Long-chain fatty acids (LCFAs) have emerged as important regulators of cancer metabolism, but their impact on hormone receptor expression in breast cancer (BCA) remains poorly understood. In this study, we investigated the effects of five LCFAs—linoleic acid (LA), oleic acid (OA), elaidic acid (EA), palmitic acid (PA), and α-linolenic acid (LNA)—on two BCA cell lines: luminal-type MCF7 and triple-negative MDA-MB-231 (MB231). All LCFAs suppressed cell viability and mitochondrial function in a dose-dependent manner, accompanied by decreased membrane potential, increased reactive oxygen species production, and a metabolic shift. Notably, OA reduced both mRNA and nuclear protein levels of estrogen receptor alpha (ERα) in MCF7 cells, leading to impaired responses to estradiol and tamoxifen. In contrast, PA induced nuclear ERα expression in MB231 cells, although ER signaling remained inactive. MicroRNA profiling revealed that OA upregulated ER-suppressive miR-22 and miR-221 in MCF7, while PA increased miR-34a in MB231, contributing to ERα induction. These findings suggest that specific LCFAs modulate ER expression through epigenetic and post-transcriptional mechanisms, altering hormonal responsiveness in BCA. Our results offer new insights into how dietary lipids may influence therapeutic efficacy and tumor behavior by regulating nuclear receptor signaling. Full article

Environmental xenobiotics, including heavy metals, endocrine-disrupting chemicals (EDCs), pesticides, air pollutants, nano- and microplastics, mycotoxins, and phycotoxins, are widespread compounds that pose significant risks to human health. These substances, originating from industrial and agricultural activities, vehicle emissions, and household products, disrupt cellular homeostasis and contribute to a range of diseases, including cancer and neurodegenerative diseases, among others. Emerging evidence indicates that epigenetic alterations, such as abnormal deoxyribonucleic acid (DNA) methylation, aberrant histone modifications, and altered expression of non-coding ribonucleic acids (ncRNAs), may play a central role in mediating the toxic effects of environmental xenobiotics. Furthermore, exposure to these compounds during critical periods, such as embryogenesis and early postnatal stages, can induce long-lasting epigenetic alterations that increase susceptibility to diseases later in life. Moreover, modifications to the gamete epigenome can potentially lead to effects that persist across generations (transgenerational effects). Although these modifications represent significant health risks, many epigenetic alterations may be reversible through the removal of the xenobiotic trigger, offering potential for therapeutic intervention. This review explores the relationship between environmental xenobiotics and alterations in epigenetic signatures, focusing on how these changes impact human health, including their potential for transgenerational inheritance and their potential reversibility. Full article

Any failure in frontonasal development can lead to malformations at the middle facial region, such as frontonasal dysplasia, midfacial clefts, and hyper/hypotelorism. Various environmental factors influence morphogenesis through epigenetic regulations, including the action of noncoding microRNAs (miRNAs). However, it remains unclear how miRNAs are involved in the frontonasal development. In our analysis of publicly available miRNA-seq and RNA-seq datasets, we found that miR-28a-5p, miR-302a-3p, miR-302b-3p, and miR-302d-3p were differentially expressed in the frontonasal process during embryonic days 10.5 to 13.5 (E10.5–E13.5) in mice. Overexpression of these miRNAs led to a suppression of cell proliferation in cultured mouse embryonic frontonasal mesenchymal (MEFM) cells as well as in O9-1 cells, a cranial neural crest cell line. Through advanced bioinformatic analyses and miRNA-gene regulation assays, we identified that miR-28a-5p regulated a total of 25 genes, miR-302a-3p regulated 23 genes, miR-302b-3p regulated 22 genes, and miR-302d-3p regulated 20 genes. Notably, the expression of miR-302a/b/d-3p—unlike miR-28a-5p—was significantly upregulated by excessive exposure to all-trans retinoic acid (atRA) that induces craniofacial malformations. Inhibition of these miRNAs restored the reduced cell proliferation caused by atRA by normalizing the expression of target genes associated with frontonasal anomalies. Therefore, our findings suggest that miR-302a/b/d-3p plays a crucial role in the development of frontonasal malformations. Full article