Search Results (2,210)

The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice. Full article

Glatiramer acetate (GA) is a first-line disease-modifying therapy for multiple sclerosis (MS) with well-established moderate efficacy and high safety, yet its mechanisms of action remain incompletely understood. DNA methylation plays a significant role in MS development and is modulated by various environmental factors, including therapeutic drugs. In this pilot study, we report the first prospective analysis of genome-wide DNA methylation changes in peripheral blood mononuclear cells (PBMCs) from four female relapsing-remitting MS patients before GA initiation and after approximately four and eight months of therapy. We identified 365 loci that are characterized by differential methylation, distinguishing post-treatment time points from baseline, with significant enrichment in CpG islands, shores, and promoter regions. Two distinct temporal patterns emerged: (1) non-monotonic DNA methylation changes peaking at four months and associated with response to foreign antigenic stimuli, and monotonic changes progressively increasing by eight months and related to mTOR-associated pathways relevant to chronic inflammation and neurodegeneration. Integration of DNA methylation and transcriptomic data revealed significant methylation-expression correlations for eight genes, including HLA-DMA, PDE4A, and SMOX—genes with established roles in MS-associated antigen presentation, immunoregulation, and neuroinflammation. Cell composition of PBMCs remained stable throughout treatment. In general, GA therapy for MS appears to induce dynamic, locus-specific DNA methylation changes in PBMCs, with distinct temporal patterns suggesting a biphasic response of the immune system. However, given that none of the individual DMPs reached genome-wide significance, the results presented in this pilot study strongly require validation in larger independent cohorts. Nevertheless, we believe that our findings provide insights into the immunomodulatory effects of GA and lay the foundation for future hypothesis-driven studies to develop epigenetic biomarkers for therapeutic monitoring and generic GA product assessment. Full article

Leydig cells (LCs) represent a somatic testicular population responsible for testosterone synthesis, a hormone essential for spermatogenesis and male fertility. The obesity condition impairs LC steroidogenic activity, contributing to testicular oxidative stress and male reproductive dysfunctions. Using a high-fat-diet (HFD) murine model, we investigated the regulatory role of the nuclear factor of activated T cells 5 (NFAT5s) in the obesity-induced LC damage and the resulting alterations in intergenerationally inherited sperm circRNA cargo. Our findings reveal a significant upregulation of both circNFAT5 and NFAT5 protein levels in HFD testis. This molecular signature correlated with decreased antioxidant defense system, increased LC apoptosis, and impaired steroidogenesis. In vitro experiments, performed in TM3 cells, confirmed that NFAT5 nuclear shuttling drives proapoptotic gene activation, while NFAT5 silencing promotes LC survival. The analysis of HFD progeny (F1H) revealed a full recovery of testis oxidative status and LC apoptosis, linked with the recovery of NFAT5 expression. However, a steroidogenic deficiency persisted in F1H offspring. Notably, HFD and F1H epididymides exhibited NFAT5 overexpression concomitantly with impaired sperm morphology, motility, viability, and altered sperm circRNA profiles alongside a deregulated 4-hydroxy-2-nonenal (4HNE) profile, a marker of sperm oxidative stress. Lastly, an enhanced FUS-related amplification of circRNA perturbations was highlighted in F1H spermatozoa. Collectively, our findings reveal a dual functional role of NFAT5 as a testicular regulator of LC fate and an epididymal sentinel of metabolic stress, in turn linking paternal obesity to the persistent transmission of sperm epigenetic anomalies across the offspring. Full article

Parathyroid carcinoma (PC) is a rare endocrine malignancy characterized by aggressive clinical behavior driven primarily by parathyroid hormone (PTH) overproduction. Standard morphological assessments frequently struggle to definitively distinguish true carcinomas from atypical benign lesions, presenting significant diagnostic challenges and a risk of overdiagnosis. Recent advances emphasize the genetic and epigenetic foundations of PC tumor biology. A central oncogenic mechanism involves the CDC73 gene, where the biallelic inactivation of CDC73 and the gain of function of mutant parafibromin—which destabilizes p53 mRNA—facilitate apoptosis evasion. Additionally, alterations in parallel pathways, such as the PI3K/AKT/mTOR cascade, and epigenetic dysregulation further contribute to disease progression. To address morphological limitations, contemporary diagnostic approaches increasingly utilize adjunctive multimarker immunohistochemical panels (including parafibromin, Ki-67, and Galectin-3) and explore emerging non-coding RNA liquid biopsy signatures. Finally, this review discusses the development of preclinical models and the application of genotype-guided targeted therapies, aiming to improve the clinical management and precision medicine strategies for PC. Full article

Breast cancer has emerged as the preeminent global health crisis in oncology, currently standing as the most frequently diagnosed malignancy among women worldwide. Establishing novel predictive biomarkers is paramount to truly personalize treatment approaches, minimize unnecessary toxicity, and significantly improve long-term outcomes for patients with breast cancer. Breast cancer transcriptomic datasets were retrieved from the Gene Expression Omnibus and processed through standardized normalization procedures. Mutation-driven regulation of SYTL4 expression, treatment response to trastuzumab, cancer hallmark enrichment, and survival associations were evaluated using established bioinformatic tools and enrichment analysis based on integrated cancer hallmark gene sets. Additionally, DNA methylation profiles were analyzed. Herein, it is shown that SYTL4 mRNA expression is significantly (p = 2.01 × 10⁻⁴) diminished in breast cancer bearing BRCA1 mutations, suggesting a mechanistic interplay between BRCA1-driven genomic instability and SYTL4-regulated signaling cascades. Kaplan–Meier survival analysis demonstrated that elevated SYTL4 mRNA expression is significantly associated with improved overall survival in HER2-positive breast cancer patients (HR = 0.72; p = 0.034). Consistently, SYTL4 expression was significantly higher in patients who responded to trastuzumab therapy, supporting its potential as a biomarker of therapeutic response. Epigenetic analysis further revealed significant differential DNA methylation of SYTL4 between tumor and unaffected control tissues (p < 2.2 × 10⁻¹⁶), with region-specific hypomethylation in tumor regulatory regions. KEGG pathway and cancer hallmark enrichment analyses indicated that genes with prominent methylation changes are involved in cytokine signaling, growth factor pathways, and extracellular matrix remodeling, with the strongest associations observed for hallmarks related to genome instability, replicative immortality, resisting cell death, and metabolic reprogramming. In summary, we present that the gene SYTL4 is a prospective biomarker for survival and trastuzumab treatment responsiveness. Our observations posit that SYTL4 expression may signify a biological milieu conducive to sustained HER2 reliance and amplified therapeutic vulnerability. Full article

Crohn’s disease (CD) is a chronic immune-mediated inflammatory disorder characterized by transmural inflammation and a progressive course that frequently leads to structural complications such as intestinal fibrosis. Fibrostenosing disease represents a major clinical challenge, affecting up to 50% of patients over time and often requiring surgical intervention. Despite advances in anti-inflammatory therapies, no effective treatments currently exist to prevent or reverse established fibrosis. Intestinal fibrosis arises from a dysregulated tissue remodeling process driven by excessive extracellular matrix deposition and persistent activation of mesenchymal cells, particularly fibroblasts and myofibroblasts. This process is orchestrated through complex interactions between immune and non-immune cells and mediated by key signaling pathways, including transforming growth factor beta (TGF-β1) and the TL1A/DR3 axis. Genetic susceptibility, notably variants in NOD2 and other fibrosis-related genes, contributes not only to disease risk but also to phenotype progression. Epigenetic mechanisms, particularly microRNAs such as the miR-29 and miR-200 families, further modulate fibrogenesis and represent promising non-invasive biomarkers. Additionally, intestinal dysbiosis and specific microbial signatures, including reduced short-chain fatty acid-producing bacteria and the presence of adherent-invasive Escherichia coli, play a critical role in promoting fibrotic pathways. Mesenteric adipose tissue, especially creeping fat, also contributes to fibrosis through immune and metabolic signaling. Emerging biomarkers related to collagen metabolism and advances in molecular profiling are improving early detection strategies. Novel therapeutic approaches targeting fibrogenic pathways, including anti-TL1A agents, show promising preliminary results. A deeper understanding of these mechanisms is essential to develop effective antifibrotic therapies and improve long-term outcomes in CD. Full article

Protein lactylation, an emerging post-translational modification (PTM) driven by the metabolite lactate, has surfaced as an important regulatory layer contributing to the crosstalk between metabolic reprogramming and cellular functional plasticity in colorectal cancer (CRC). Within the unique “host–microbiota” symbiotic microenvironment of CRC, the Warburg effect—fueled jointly by oncogene activation and microbial metabolism—provides abundant substrates for lactylation. This modification is dynamically regulated by a complex enzymatic system comprising “Writers” (e.g., p300/CREB-binding protein [p300/CBP], alanyl-tRNA synthetase 1/2 [AARS1/2]) and “Erasers” (e.g., histone deacetylases [HDACs] and Sirtuins). Through intricate crosstalk with other PTMs, such as acetylation and ubiquitination, lactylation exerts critical regulatory effects on both the histone epigenetic landscape and non-histone protein functions. Functionally, lactylation not only drives malignant proliferation, invasion, and metastasis but also systematically remodels the immunosuppressive “cold” tumor microenvironment. Furthermore, it confers broad-spectrum resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by orchestrating a ferroptosis defense network, enhancing DNA damage repair (DDR), and activating protective autophagy. This review systematically synthesizes the regulatory networks and biological functions of lactylation in CRC, deeply elucidating the core mechanisms underlying therapy resistance. Finally, we discuss the clinical translational potential of lactylation as a novel diagnostic/prognostic biomarker and therapeutic target, aiming to provide new theoretical foundations and strategic directions for overcoming current bottlenecks in CRC clinical treatment. Full article

Ultraviolet radiation (UVR) exposure accelerates skin aging by disrupting cellular homeostasis and inducing epigenetic changes, such as promoter hypermethylation of key regulatory genes. However, the molecular mechanisms underlying UVR-driven epigenetic silencing remain poorly understood. By integrating high-throughput DNA methylation profiling with co-regulatory network analysis, we identified KIT as a hub gene in a photoaging-associated methylation module. Pathway enrichment further revealed coordinated hypermethylation of the canonical Wnt/β-catenin signaling pathway, establishing the Wnt/KIT axis as a critical epigenetic-signaling nexus in UVR-induced skin fibroblast aging. In immortalized human skin fibroblasts (HSFs), UVR suppressed Wnt signaling, leading to KIT promoter hypermethylation, transcriptional silencing, and premature photoaging. Gain-of-function studies revealed that reversing KIT hypermethylation either via Wnt pathway activation or KIT overexpression effectively mitigated photoaging-associated phenotypes. Crucially, we found that puerarin (PUE), a natural isoflavone, reversed UVR-induced epigenetic silencing by directly interacting with β-catenin, reactivating Wnt signaling, and restoring KIT expression. PUE treatment preserved cellular function in UVR-damaged fibroblasts. These findings establish the Wnt/β-catenin-KIT axis as a critical epigenetic driver of skin aging and highlight puerarin as a promising therapeutic candidate for targeted anti-aging intervention. Full article

Post-infectious bronchiolitis obliterans (PIBO) is a severe chronic airway disease in children following lower respiratory tract infections. Human adenovirus (HAdV) and Mycoplasma pneumoniae (MP) are the major associated pathogens, with geographic variations in their relative importance. This review analytically compares the mechanistic divergence and convergence between HAdV and MP. Both pathogens converge on MyD88/NF-κB/MAPK signaling and neutrophil-driven inflammation, but diverge in initial host engagement (CAR/integrins vs. TLR2/6 and CARDS toxin) and inflammasome activation (TLR9-related vs. NLRP3-related). This review aims to propose an integrative model linking acute immune activation to fibrotic bronchiolar narrowing and to evaluate the risk factors for PIBO. Genetic susceptibility and epigenetic regulation help explain population differences in PIBO risk and geographic distribution. Despite progress, significant knowledge gaps remain, including the lack of single-cell resolution studies, the absence of co-infection animal models, and uncertainty regarding the long-term efficacy of targeted immunomodulatory therapies. Addressing these gaps is essential for improving early diagnosis and clinical outcomes. Full article

Endometrial cancer (EC) is increasingly recognized as a heterogeneous disease, yet current treatment strategies often fail to explain why tumors with similar molecular profiles respond differently or develop resistance. This gap points to regulatory mechanisms beyond static genomic alterations. Epigenetic dysregulation through DNA methylation, histone modification, and non-coding RNA (ncRNAs) networks acts as a dynamic and reversible system that governs how tumors adapt under therapeutic pressure. In EC, alterations affecting key regulators such as MLH1, PTEN, and hormone receptors directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment, defining treatment-responsive and treatment-resistant states. These observations shift the role of epigenetics from a descriptive feature of tumor biology to a determinant of therapeutic behaviour. Epigenetic states influence immune recognition, pathway activation, and cell cycle control, thereby shaping response to chemotherapy and immune checkpoint blockade. Biomarkers derived from these alterations, including methylation signatures and circulating RNAs, offer opportunities for patient stratification and longitudinal monitoring of treatment response. Therapeutically, targeting epigenetic regulators provides a strategy to reverse resistance and restore treatment sensitivity. DNA methyltransferase and histone deacetylase inhibitors, particularly in combination with established therapies, have shown potential to enhance treatment efficacy. Emerging approaches, including locus-specific epigenetic editing and liquid biopsy–guided monitoring, further support adaptive treatment strategies. Integrating epigenetic reprogramming into clinical decision-making offers a practical path toward improving treatment response and overcoming resistance in EC. Here, we propose an Epigenetic State–Response Framework (ESRF) in which dynamic epigenetic states define treatment-sensitive and resistant phenotypes, map to specific therapeutic vulnerabilities, and can be actively reprogrammed to restore treatment response. Full article

Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug–herb interactions with standard anticancer agents—namely sorafenib—remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments. Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-α via nuclear factor-kappaB (TNF/NF-κB), mitogen-activated protein kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK–STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group. Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling. Full article

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS. Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring. Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS. Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition. Full article

Plant-derived bioactive compounds represent a major foundation of modern anticancer therapy and remain a prolific source of molecules with clinically relevant activity. This review provides an integrated classification of plant-derived anticancer compounds based on their clinical development status and predominant molecular mechanisms of action. Established chemotherapeutic agents, including taxanes, vinca alkaloids, and camptothecin derivatives, are distinguished from investigational phytochemicals such as polyphenols, flavonoids, terpenoids, and alkaloids that are under preclinical or clinical evaluation. These compounds target key hallmarks of cancer through modulation of microtubule dynamics, inhibition of topoisomerases, regulation of oncogenic signaling and epigenetic processes, and suppression of angiogenesis, invasion, and metastasis. Particular emphasis is placed on multitarget phytochemicals that interfere with PI3K/Akt, NF-κB, JAK/STAT, and MAPK pathways, induce apoptosis, and promote epigenetic reprogramming. In addition, major translational challenges, especially limited bioavailability, are discussed alongside advances in nano-enabled delivery systems designed to enhance therapeutic efficacy and reduce systemic toxicity. Collectively, this framework highlights the continuing relevance of plant-derived compounds in oncology and supports their rational integration into precision cancer therapy. Full article

Drug resistance represents one of the most critical challenges in modern medicine, undermining the efficacy of therapies across both bacterial infections and cancer. Although these conditions arise in fundamentally distinct biological systems, they are governed by shared evolutionary pressures that drive the emergence and selection of resistant populations. This narrative review provides an integrative, cross-disciplinary perspective on drug resistance, focusing on bacteria and cancer and emphasizing the shared evolutionary and molecular mechanisms underlying treatment failure in both domains. Key resistance strategies include efflux-mediated drug export, target modification, enzymatic drug inactivation, metabolic reprogramming, epigenetic and transcriptional plasticity, and protection conferred by specialized microenvironments. These processes are further reinforced by phenotypic heterogeneity, including bacterial persister cells and cancer stem-like cells, which contribute to recurrence and multidrug resistance. Collectively, these parallels define drug resistance as a convergent evolutionary phenomenon driven by adaptability under selective pressure. Recognizing these shared mechanisms reveals important translational opportunities for therapeutic intervention. Strategies such as combination therapy, drug repurposing, nanotechnology-enabled delivery systems, and host-directed approaches offer promising avenues to prevent, delay, or overcome resistance. By integrating insights from microbiology and oncology, this review proposes a unified framework for resistance biology and highlights the potential of cross-disciplinary strategies to improve treatment durability and clinical outcomes. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies and immunotherapies, clinical outcomes remain poor owing to profound molecular heterogeneity, intrinsic therapeutic resistance, and complex immune evasion mechanisms. Although genomic profiling has identified recurrent alterations in HCC, large-scale functional validation of candidate drivers and vulnerabilities remains challenging. CRISPR (clustered regularly interspaced short palindromic repeats)-based screening technologies have transformed this landscape by enabling systematic interrogation of gene function in physiologically relevant contexts. In this review, we summarize recent studies that have applied CRISPR screening approaches in HCC research. These efforts have uncovered multilayered dependency programs that govern ferroptosis resistance, metabolic reprogramming, epigenetic regulation, tumor suppressor networks, immune evasion, and resistance to targeted therapies. We also discuss the major limitations of current studies, including model bias, incomplete representation of HCC heterogeneity, and technical constraints intrinsic to pooled screening. Overall, integration of CRISPR screening with patient-derived models, single-cell readouts, and precision editing technologies is expected to accelerate mechanistic discovery and biomarker-guided therapeutic prioritization for HCC. Full article