The extracellular matrix (ECM) is a highly organised and dynamic regulator of tissue structural integrity and biochemical signalling, and its dysregulation is a hallmark of fibrosis and cancer. Recent evidence highlights the critical role of epigenetic mechanisms in controlling ECM-related gene expression and remodelling activity. This review integrates recent advances in understanding how epigenetic mechanisms govern ECM composition, remodelling, and mechanotransduction, and how reciprocal ECM-derived signals reshape the epigenetic landscape. Growing evidence links DNA methylation, histone modifications, and non-coding RNAs to the regulation of key ECM components, matrix-modifying enzymes, and stiffness-associated signalling pathways, including TGF-β, Wnt, and PI3K/Akt are summarised in this review. The bidirectional feedback between altered ECM mechanics and epigenetic enzyme activity is emphasised, showing how matrix stiffening and aberrant epigenetic programming cooperatively drive pathological tissue remodelling and tumour progression. This review summarises findings from in vitro systems, animal models, and human disease studies that illustrate the functional consequences of ECM-epigenetic crosstalk. The emerging therapeutic approaches targeting the ECM-epigenetic axis, including epigenetic modulators and ECM-directed interventions, outline current challenges and future directions for restoring matrix homeostasis in disease. Together, this review provides an integrated framework for understanding the bidirectional ECM-epigenetic interactions and their translational relevance in molecular biomedicine.

Leptomeningeal disease (LMD) is a devastating complication of advanced solid tumors with limited prognostic and response-assessment tools. Because LMD molecular evolution is frequently compartmentalized behind CNS barriers, cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) may provide CNS-specific molecular readouts of disease activity. We evaluated whether baseline CSF ctDNA profiles and longitudinal ctDNA kinetics associate with survival in LMD.

Originally reported as an oncogene and currently known to be a major "genome guardian", the p53 protein remains one of the most explored transcription factors, exhibiting variety of functions both within transcription regulation and beyond. Given that p53 dysfunction contributes to the majority of human cancers, understanding its regulatory mechanisms and therapeutic potential remains a primary research focus. This review addresses the key aspects of p53 regulation and functionality, analyses its role in tumor evolution, and provides a comprehensive analysis of current and emerging therapeutic strategies targeting the p53, with particular emphasis on immunotherapy approaches.

Mycotoxins are toxic secondary metabolites produced predominantly by fungal genera, such as Aspergillus, Fusarium, and Penicillium, and represent major foodborne contaminants responsible for chronic human exposure worldwide. While aflatoxin B1 (AFB1) is a well-established hepatocarcinogen, increasing evidence indicates that multiple mycotoxins contribute to tumorigenesis across diverse organ systems through shared biochemical and molecular mechanisms. At the molecular level, mycotoxins undergo cytochrome P450-mediated bioactivation, generating reactive intermediates that induce DNA adduct formation, oxidative stress, genomic instability, and disruption of redox homeostasis. These events converge on dysregulation of key signaling pathways governing cell-cycle control, apoptosis, immune surveillance, and epigenetic regulation, including aberrant DNA methylation, histone modification, and non-coding RNA expression. Importantly, emerging data support a "dual-hit" paradigm in which mycotoxin exposure synergizes with oncogenic viral infections, such as hepatitis B virus (HBV), human papillomavirus (HPV), and Epstein-Barr virus (EBV), amplifying genotoxic stress, immune evasion, and epigenetic instability. This review synthesizes current mechanistic insights into mycotoxin-induced carcinogenesis, emphasizing molecular toxicological endpoints that link exposure to cancer risk. In addition, advances in biosensing, detoxification, and preventive strategies are discussed, highlighting the need for mechanism-driven interventions to mitigate mycotoxin-associated carcinogenicity and its public health burden.

Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling-driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications-plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This moderate oxidative stress promotes tumorigenesis by inducing DNA damage, genomic instability, and aberrant activation of proliferative and survival pathways, while also contributing to resistance to conventional therapies. Paradoxically, excessive ROS accumulation can overwhelm antioxidant defenses, triggering oxidative stress-induced programmed cell death (PCD) mechanisms, including apoptosis, autophagy, and ferroptosis. Owing to its dual role-facilitating both tumor progression and suppression-ROS have emerged as compelling yet complex targets in cancer therapy. Therapeutic strategies aimed at modulating ROS homeostasis, such as enhancing ROS production, inhibiting antioxidant systems, or targeting downstream redox-regulated signaling nodes, hold promise for selectively eliminating cancer cells. Furthermore, integrating redox profiling or "redox signatures" into personalized medicine approaches may optimize therapeutic efficacy while minimizing off-target toxicity. In this review, we critically examine the Janus-faced role of ROS in carcinogenesis, dissect the molecular pathways regulated by ROS in tumor biology, and explore current advancements, limitations, and future directions in redox-based anticancer therapeutic approaches.

The cGAS-STING pathway is crucial for recognizing aberrant DNA in the cytoplasm and activating the innate immune response. After detecting aberrant DNA in the cytoplasm, cGAS can catalyze the synthesis of cGAMP from ATP and GTP, which acts as a second messenger to engage STING and unleash type I interferons, thereby eliciting a robust antitumor immune cascade. In recent years, the role of the cGAS-STING pathway in tumor immunity has attracted widespread attention. Paradoxically, it not only activates antitumor immune responses but also promotes tumor progression under certain circumstances. This review untangles the safeguards that prevent cGAS from recognizing nuclear self-DNA, delineates the antitumor and pro-tumor mechanisms of the cGAS-STING axis, and surveys tumor immunotherapy strategies targeting this pathway.

DEAD-box RNA helicase 3 (DDX3) is a key regulator of RNA metabolism whose role in cancer extends beyond canonical RNA unwinding and translational control. Emerging evidence indicates that DDX3 functions as a context-dependent post-transcriptional integrator coordinating adaptive programs essential for malignant progression. Rather than acting as a classical oncogene or tumor suppressor, DDX3 shapes cancer phenotypes by synchronizing immune regulation and mitochondrial plasticity at the RNA level. This review summarizes recent mechanistic and translational studies illustrating how DDX3 orchestrates tumor immune evasion, metabolic adaptation, and therapy resistance through post-transcriptional regulation. We highlight DDX3-mediated modulation of immune signaling and immune checkpoint dynamics, particularly its 3' untranslated region-dependent control of PD-L1 cell-surface presentation, which critically influences tumor immune surveillance and responsiveness to immunotherapy. In parallel, we discuss how DDX3 governs mitochondrial homeostasis, dynamics, and bioenergetic flexibility by selectively regulating stress-responsive transcripts, enabling cancer cells to withstand metabolic and oxidative stress. We further propose an integrative framework in which immune escape and mitochondrial plasticity are coordinately regulated by DDX3-centered RNA regulatory networks. This model reconciles the context-dependent roles of DDX3 across cancer types and disease stages and highlights DDX3 as a systems-level regulator and a potential target for precision combination therapies.

Germline biomarker testing to assess inherited risk for developing malignancy has evolved quickly from testing for 1 or 2 genes from a few laboratories to ordering panels of 80 or more genes available from multiple laboratories. Many health professionals did not receive foundational information in training yet are expected to identify and manage care for individuals and families with germline risk. Errors in testing do occur and can have significant adverse consequences including missed opportunities for prevention and detection for the patient and family, unnecessary risk-reducing surgery, and even death. By better understanding these errors and underlying causes, as well as the potential negative consequences due to these errors, strategies can be developed to help prevent future harm to patients.

This narrative review examines DNA methylation dysregulation in pancreatic cancer, focusing on its mechanistic roles in tumorigenesis and applications in biomarkers and therapies.

Poly(aneu)ploidy is a potent source of cellular stress that typically leads to loss of fitness, premature aging/senescence, and cell death. Yet in some systems, most notably microbial pathogens and human cancer cells under poly(aneu)ploidogenic stress, cells can adaptively remodel their phenotype, resist damage, and even convert this stress into a selective advantage. This mini-review examines current knowledge on the mechanisms underlying these adaptive responses in cancer cell communities and how poly(aneu)ploid subpopulations reshape the behavior of the entire population. Because poly(aneu)ploidy is almost invariably coupled to changes in cell size and morphology, we place particular emphasis on biophysical and mechanobiological adaptations. These include physico-chemical reprogramming, proteome remodeling, volume gain, membrane stretching, altered endocytosis, community-level metabolic rewiring, engagement of the nucleus as a key mechanosensor, and the role of mechanoreceptor channels. Finally, we discuss emerging therapeutic strategies that seek to exploit the specific vulnerabilities of poly(aneu)ploid cells. Together, these insights highlight the central role of poly(aneu)ploidy in enabling tumor adaptation and evolution, and point to new avenues for understanding cancer cell biology and designing future treatment strategies.

Decitabine (DEC) and Venetoclax (VEN) are approved for elderly adult acute myeloid leukemia (AML) patients with an additional sex comb-like 1 (ASXL1) mutation who cannot tolerate intensive chemotherapy. However, direct comparative data in this population remain limited. A systematic review and meta-analysis were conducted to assess the indirect efficacy of DEC alone and VEN in older AML patients with ASXL1 mutations. A matched cohort was created by comparing outcomes of consecutive adults with AML who received DEC or DEC with VEN after propensity score matching using the nearest-neighbor methodology. The DEC + VEN cohort had a lower early mortality rate than the DEC cohort (30-day mortality: 2.7%-5% vs. 9.7%, p = 0.01; RR = 0.90, 95% CI 0.83-0.97 versus RR = 0.97, 95% CI 0.92-1.02). However, the 30-day and 60-day mortality rates were similar between groups (9.5% vs. 2.7%, p = 0.17; 18.9% vs. 9.5%, p = 0.16). Overall survival (OS) was measured at 7.9-25.1 months. The DEC + VEN cohort had significantly higher response rates than the decitabine cohort. According to the 2017 EL N Genetic Risk classification, people with a favorable moderate risk had a higher rate of complete response or complete response with incomplete hematologic recovery than those with high risk (65% vs. 34%). The use of DEC for 5 or 10 days as the hypomethylating agents combination with VEN did not affect the CR/Cri rate. In conclusion, DEC plus VEN was associated with improved clinical responses and survival signals in ASXL1-mutated AML, warranting prospective confirmation.

Cholangiocarcinoma (CCA) continues to be classified as a rare cancer with high mortality rates, underscoring the urgent need for more effective systemic treatment strategies. The widespread implementation of next-generation sequencing has enabled comprehensive characterization of the genomic landscape of CCA, revealing a relatively high prevalence of actionable genetic alterations.

Small cell lung cancer (SCLC) initially responds well to cisplatin-based chemotherapy, but rapid development of drug resistance limits long-term efficacy and subsequent treatment options. Understanding the multifactorial mechanisms of cisplatin resistance is essential for improving patient outcomes. This review synthesizes recent preclinical and clinical advances, focusing on seven key resistance mechanisms and emerging therapeutic strategies, including immunotherapy, targeted therapy, and novel chemotherapeutic agents.

Early detection of gastrointestinal (GI) cancers remains a critical unmet clinical need, as most patients are diagnosed at advanced stages when prognosis is poor. Liquid biopsy has emerged as a transformative approach for minimally invasive cancer detection by analysing tumour-derived analytes in blood and other body fluids. Recent advances in circulating tumour DNA (ctDNA) sequencing, cell-free DNA methylation profiling, fragmentomics, extracellular vesicle and exosome characterisation, circulating tumour cell isolation and tumour-educated platelets have markedly improved sensitivity and specificity for detecting incipient malignancies. Despite these advances, sensitivity in stage I disease remains limited due to low tumour burden and minimal analyte scaling, resulting in false-negative results for small or indolent lesions. In addition, clonal haematopoiesis derived alterations can confound mutation-based assays, highlighting the need for epigenetic and multi-analyte approaches to improve specificity. Ultimately, widespread clinical adoption will require standardised, prospective trials demonstrating diagnostic accuracy and a reduction in cancer-specific mortality. Multi-analyte and machine learning-driven approaches, integrating DNA, RNA, protein and epigenomic signals, are now in late-stage clinical trials and poised for clinical translation. United States Food and Drug Administration approvals of blood-based colorectal cancer screening tests and laboratory-developed assays for hepatocellular carcinoma exemplify the translational momentum in this field. Here, we review the current landscape of liquid biopsy biomarkers for GI cancers, emphasising technological innovations, clinical performance and ongoing trials. We also discuss key challenges, including sensitivity in stage I disease, specificity amidst clonal haematopoiesis and integration with established screening paradigms. The continued evolution of assay technologies and translational research heralds a paradigm shift towards precision early detection of GI cancers, with the potential to substantially reduce mortality through earlier intervention. KEY POINTS: Liquid biopsy technologies are advancing rapidly for early detecion of GI cancers, using ctDNA, methylation profiling, fragmentomics, EVs, CTCs, and TEPs. Limited sensitivity in stage I disease remains a key barrier, largely due to low tumor burden and analyte scarcity. Clonal hematopoieses confounds mutation-based assays, emphasizing the need for epigenetic and multi-analyte strategies to improve specificity. Multi-analyte, machine-learning-driven platforms are nearing clinical translation, supported by late-stage trials and recent FDA approvals.

Pituitary neuroendocrine tumours (PitNETs) range from slow-growing to highly aggressive tumours; however, traditional prognostic markers often fail to predict clinical outcomes reliably. DNA methylation has recently emerged as a promising biomarker for assessing tumour behaviour. This systematic review evaluates its predictive value in PitNETs. To systematically assess the clinical applicability of DNA methylation profiles in predicting behaviour of PitNETs. Systematic review. A comprehensive search was conducted in Medline, Embase, Web of Science, and Cochrane CENTRAL on December 13, 2024, with an update on October 17, 2025. The search included studies on adult PitNET patients, specifically examining tumour behaviour in relation to DNA methylation. Excluded were studies that focused on cell-free DNA, investigated a single gene with no established relevance to tumour behaviour, or assessed tumour size only. Data were extracted from 20 eligible studies by four independent reviewers. The risk of bias was assessed using the QUIPS tool. Due to methodological differences across studies, the findings were summarised narratively. Twelve studies investigated tumour invasiveness, two examined tumour aggressiveness and five examined PitNET regrowth, recurrence and re-intervention. The majority of studies concentrated on non-functioning PitNETs and used Illumina arrays or PCR-based methods. These analyses identified several differentially methylated genes linked to invasiveness (e.g., PHYHD1, WNT4, STAT6, CDH1, CDH13), aggressive behaviour (e.g., AIP, PDCD1, LINE-1), and tumour regrowth (e.g., TERT, FAM90A1, ING2). DNA methylation profiling shows potential for predicting PitNET behaviour, but methodological inconsistencies limit its clinical application. Standardized methods and prospective validation are needed for clinical integration.

Replicative single-stranded DNA gaps are emerging as central intermediates in the cellular response to replication stress. Replication frequently continues past lesions or difficult-to-replicate regions through leading-strand repriming or delayed Okazaki fragment (OKF) maturation, generating structured gaps requiring stabilization and repair. Here, we describe the major routes of gap formation, including polymerase-helicase uncoupling, impaired OKF processing, PrimPol-mediated lesion bypass, and endogenous abasic site accumulation from base excision repair and DNA methylation turnover. We examine the mechanisms that suppress, protect, and resolve these gaps, highlighting RAD51/BRCA2-mediated stabilization, PCNA modifications, PARP1- and CTC1-STN1-TEN1 (CST)-dependent fill-in pathways, and the balance between translesion synthesis and template switching. Finally, we discuss how persistent gaps drive fork degradation, genome instability, and innate immune activation, contributing to explaining the therapeutic vulnerabilities and resistance of cancer cells to PARP, polymerase Q (Pol θ), and ATR inhibitors. This perspective presents a unified model in which timely replicative gap recognition and resolution ensure genome stability.

Interest in RNA editing has emerged in molecular medicine due to its widespread dysregulation and therapeutic potential. Its regulatory mechanisms in governing non-coding RNAs, especially microRNAs (miRNAs) remain largely unresolved. Emerging evidence in diseases reveals a functional convergence between miRNAs and polyamine metabolism, two systems traditionally studied separately. miRNAs serve as primary substrates for adenosine deaminase acting on RNA (ADAR) which could regulate polyamine metabolism via the sirtuin (SIRT1)-p53 axis, forming a disease-relevant loop. Indeed, in many proliferative malignancies, hyper-editing of miRNAs coincides with high polyamine levels and promotes SIRT1-mediated p53 deacetylation. Conversely, in many age-related diseases, hypo-editing and polyamine loss blunt this pathway. This review dissects this emerging ADAR-editing-miRNA-polyamine circuit anchored on the SIRT1-p53 axis. We propose this as a unifying working model to integrate disparate correlative observations, providing a roadmap for future validation studies to confirm its potential for combinatorial therapeutic targets and diagnostic biomarkers.

Head and neck squamous cell carcinoma (HNSCC) arises from the squamous epithelium of the head and neck region, comprising heterogeneous lesions with distinct risk factors and diverse genetic and epigenetic alteration patterns. HNSCC is often difficult to control when lymph node metastasis has occurred, and treatment outcomes remain unsatisfactory. Elucidating the genetic and epigenetic profiles of cancer-associated genes is essential for improving clinical outcomes, yet to date the key molecules driving HNSCC progression remain unclear.

MicroRNAs (miRNAs) are ~ 22-nucleotide-long noncoding RNAs that regulate gene expression at the post-transcriptional level through mRNA cleavage or translational repression. To date, approximately 2,700 mature human miRNAs have been identified, although biological functions have been assigned to fewer than 600. Among these, miR-155 has emerged as a regulatory miRNA with important roles in metabolism, immune homeostasis, and disease pathogenesis. Dysregulated miR-155 expression has been implicated in metabolic disorders, including diabetes and preeclampsia, as well as autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Mechanistic and preclinical evidence indicates that aberrant miRNA-155 expression contributes to tumorigenesis by modulating tumor suppressor genes in hematologic malignancies and solid tumors. This review summarizes the current updates on the physiological and pathological roles of miRNA-155.

MicroRNAs (miRNAs/miRs) are critical post‑transcriptional regulators of gene expression. Aberrant miRNA expression has been closely linked to the initiation and progression of a wide range of malignant and non‑malignant disorders, prompting extensive investigation into their biological functions, regulatory mechanisms and clinical relevance. Among these molecules, miR‑205 has attracted considerable attention owing to its unique expression patterns and context‑dependent roles. Notably, miR‑205 participates in epigenetic regulation, functions as either a tumor suppressor or oncogene, contributes to therapeutic resistance and exerts important effects on non‑cancerous diseases. The present review provides a comprehensive overview of the current understanding of miR‑205 in both malignant and non‑malignant conditions, highlights its major target genes and associated signaling pathways, and discusses its potential utility in the development of precise diagnostic, prognostic and therapeutic strategies.