Search Results (1,267)

Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation and has emerged as a key mechanism of neuronal injury across a broad spectrum of neurological disorders. MicroRNAs (miRNAs), which function primarily as post-transcriptional regulators of gene expression, are increasingly recognized as important modulators of the regulatory networks governing ferroptosis and as potential therapeutic targets in these conditions. In this review, we synthesize current advances in miRNA-mediated regulation of ferroptosis in neurological disorders. We first outline the core molecular pathways governing ferroptosis, with particular emphasis on antioxidant defense, lipid peroxidation, and iron metabolism. We then integrate evidence from ischemic stroke, intracerebral hemorrhage, epilepsy, toxic encephalopathy, spinal cord injury, Parkinson’s disease, and Alzheimer’s disease, to illustrate how disease-specific miRNA regulatory axes shape ferroptotic vulnerability and its pathological consequences in distinct neurological settings. Importantly, we highlight exosome-based strategies targeting ferroptosis-related miRNA networks as a promising therapeutic approach for neurological disorders, with demonstrated neuroprotective and functional benefits in preclinical studies. Collectively, current evidence supports miRNA-mediated regulation of ferroptosis as an important mechanistic framework and a promising therapeutic target in neurological disorders. Full article

Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-related morbidity and mortality, and reliable biomarkers for early diagnosis and risk stratification are still lacking. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) can regulate gene expression through competing endogenous RNA (ceRNA) interactions, but OSCC-specific ceRNA axes with clinical relevance are still poorly defined. We integrated lncRNA, miRNA, and mRNA expression data from six OSCC-related datasets in the Gene Expression Omnibus with in silico interaction predictions to construct an OSCC-focused ceRNA network and examine its association with survival. The resulting network comprised 8 mRNAs, 22 miRNAs, and 12 lncRNAs. Within this network, we identified a previously unrecognized XIST–miRNA–ZNF662 axis that has not been characterized in OSCC. ZNF662 was consistently downregulated in tumors, and higher ZNF662 expression was associated with improved survival in an independent head and neck squamous cell carcinoma cohort. Components of the XIST–miRNA–ZNF662 axis also showed excellent diagnostic performance for distinguishing OSCC from normal samples across (Gene Expression Omnibus) GEO datasets, highlighting a ceRNA module with promising diagnostic and prognostic potential that could be explored further in non-invasive biofluids. Full article

MicroRNAs (miRNAs) play important roles in the regulation of gene expression and are frequently dysregulated in cancer. Among them, the miR-196 family has been implicated in multiple malignancies, including colorectal cancer (CRC), but the isoform-specific transcriptional effects of miR-196A and miR-196B remain poorly understood. In this study, we generated miR-196A and miR-196B knockout SW48 CRC cell lines using CRISPR-based genome editing and performed RNA sequencing to investigate the transcriptional consequences of individual miR-196 isoform deletion. Transcriptomic analysis revealed widespread gene expression changes in both knockout models and demonstrated distinct clustering patterns between parental SW48 cells and miR-196-deficient cells. Functional enrichment analysis indicated that the altered genes were associated with biological processes related to cytoskeletal organization, intracellular transport, protein folding, and metabolic regulation. Notably, both shared and isoform-specific transcriptional alterations were observed, suggesting that miR-196A and miR-196B contribute to partially overlapping but distinct regulatory networks in CRC cells. Collectively, these findings provide a comprehensive transcriptomic overview of miR-196 isoform deletion in colorectal cancer cells and highlight potential isoform-dependent transcriptional programs that may contribute to CRC biology. Full article

Acute lymphoblastic leukemia (ALL) is a clinically diverse cancer in which microRNA (miRNA)-mediated post-transcriptional regulation contributes to leukemogenesis and subtype heterogeneity. In this study, miRNA expression profiling by microarray was performed on ALL cases (B-ALL and T-ALL) and healthy controls. Data were normalized and analyzed for differential expression using false discovery rate (FDR)-adjusted p-values. Differentially expressed miRNAs were further examined using unsupervised visualization to assess overall disease-related expression patterns. To explore their biological significance, experimentally validated miRNA–target interactions were obtained using multiMiR, limited to validated databases (miRTarBase, TarBase, and miRecords) and summarized via target-burden ranking, miRNA–target network analysis, and Circos–style interaction mapping. A unique miRNA expression signature was identified in ALL. Upregulated miRNAs included miR-106a-5p, miR-106b-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-181b-5p, and miR-128-3p, while miR-127-3p, miR-139-5p, miR-433-3p, and miR-584-5p were downregulated. Validated targets concentrated on key leukemia-related genes like PTEN, BCL2L11, CDKN1A, CCND1, RB1, E2F1, and TGFBR2. KEGG pathway analysis highlighted pathways associated with leukemic cell survival and growth, including MAPK, cell cycle, autophagy, Hippo, ubiquitin-mediated proteolysis, and mTOR signaling pathways. These findings reveal a concise ALL-associated miRNA panel predominantly comprising the miR-17/20/106 family and provide a prioritized set of candidate regulatory networks for subtype-specific validation and functional follow-up studies. Full article

Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease affecting the axial skeleton, characterized by progressive structural damage and functional impairment. Although biologic therapies targeting tumor necrosis factor and interleukin-17 have improved clinical outcomes, a substantial proportion of patients fail to achieve sustained disease control. Emerging evidence suggests that metabolic alterations may contribute to AS pathogenesis; however, systematic characterization of metabolism-related biomarkers and their regulatory networks remains limited, and the interplay between metabolic dysfunction and immune dysregulation in AS is poorly understood. Two whole-blood GEO datasets (GSE25101, GSE73754; n = 104) were integrated as the primary analytical cohort. A third dataset (GSE11886, n = 18; monocyte-derived macrophages) was included for exploratory cross-tissue analysis. Differential expression analysis identified 847 DEGs, which were refined to 16 metabolism-related genes through weighted gene co-expression network analysis (WGCNA) and GeneCards database filtering. Eleven machine learning algorithms with 5-fold cross-validation were applied to construct diagnostic models and identify hub genes. Validation analyses included immune cell infiltration estimation using CIBERSORT, metabolic pathway activity assessment via ssGSEA, single-cell transcriptomics from GSE268839, functional enrichment through GSEA/GSVA, and chromosomal localization analysis. A competing endogenous RNA (ceRNA) regulatory network was constructed to map post-transcriptional regulation. Natural compounds from 66 AS-treating traditional Chinese medicines were screened against hub genes using deep learning-based binding prediction. Multiple machine learning algorithms achieved comparable cross-validated performance (CV AUC range 0.741–0.836; top five models: 0.805–0.836) using the six hub genes (MFN2, SLC27A3, RHOB, SMG7, AKR1B1, LCOR) identified through SHAP-based feature importance analysis of the PLS model. Leave-one-dataset-out validation between the two whole-blood cohorts showed that all algorithms exceeded an AUC of 0.77 in Round 1 (validate: GSE73754, n = 72; best AUC 0.861), while Round 2 (validate: GSE25101, n = 32) yielded more modest performance (best AUC, 0.715) reflecting the smaller validation sample. Exploratory application to GSE11886 (macrophage-derived samples) showed near-chance performance, consistent with the tissue-source discrepancy. AS patients exhibited significant downregulation of oxidative phosphorylation, TCA cycle, and glycolysis pathways (p < 0.01), accompanied by elevated glutathione metabolism (p < 0.001). Immune cell deconvolution revealed reduced CD8+ T cell proportions correlating with MFN2 downregulation, and increased neutrophil frequencies correlating with SLC27A3 upregulation. Exploratory single-cell analysis indicated that RHOB expression was relatively enriched in border-associated macrophages and fibroblasts, while AKR1B1 was more prominently expressed in vascular endothelial cells and plasmacytoid dendritic cells. The ceRNA network identified 21 miRNAs and 65 lncRNAs forming 86 regulatory interactions, with four key regulatory axes (SATB1-AS1/miR-539-5p/LCOR, FAM95B1/miR-223-3p/RHOB, LINC01106/miR-106a-5p/MFN2, AATBC/miR-185-5p/SMG7) predicted to regulate hub gene expression. Compound screening identified betaine, pyruvic acid, citric acid, etc., as top-ranking candidates, with MFN2 showing the highest binding capacity among hub genes. This study provides an integrative framework linking metabolic reprogramming with immune dysfunction in AS. The six-gene diagnostic signature showed preliminary discriminatory ability in the available datasets, while the ceRNA regulatory network and natural compound screening results prioritize candidate regulatory pathways and compounds for future validation. These findings advance our understanding of AS pathogenesis and may guide future biomarker development and targeted intervention strategies. Full article

Background/Objectives: Although clinically distinct, bipolar disorder (BP), schizophrenia (SZ), major depressive disorder (MDD), and social anxiety disorder (SAD) share fundamental biology. We mapped these transdiagnostic systemic mechanisms. Methods: Weighted Gene Co-Expression Network Analysis (WGCNA) of peripheral blood RNA-Seq datasets evaluated module preservation, hub gene disruption, and microRNA (miRNA) networks. Results: Seven modules showed robust cross-disease preservation. Overall, 56 of 105 candidate hub genes exhibited altered expression, with 22 passing the false discovery rate (FDR) correction. Hubs like IL1B, TLR2, and MMP9 dominated networks linked to altered inflammatory signaling and structural remodeling. Downregulated ribosomal hubs characterized systemic metabolic stress. Discussion: These signatures capture extensive systemic dysregulation. Inflammation and metabolic shifts correlate strongly with pathways regulating chronic neuroinflammation, epigenetic control, and dendritic pruning. Computational models suggest these cascades evade miRNA controls, potentially compromising structural neural plasticity. Conclusions: This shared transcriptomic architecture challenges rigid diagnostic boundaries. Identifying systemic immune dysregulation and translational alterations as core pathogenic denominators provides a rationale for transdiagnostic therapies targeting upstream systemic networks to mitigate neural vulnerabilities. Full article

Non-small-cell lung cancer (NSCLC) constitutes approximately all lung cancers (LCs), and metastasis remains a major challenge in its treatment, thus necessitating the detection of novel molecular players involved in this process. In this study, we performed a comprehensive analysis of microarray and RNA-seq cohorts extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) and associated them with metastasis-related genes involved in brain metastasis (BM) in NSCLC. We thus identified differentially expressed metastatic genes (DEMGs) and constructed a protein–protein interaction network (PPIN) using these DEMGs. These DEMGs were further analyzed for associations with patient age, gender, and tumor stage, and the significant impact of specific genes on overall survival (OS) was assessed to determine the prognostic significance of the identified targets. We finally constructed a three-node microRNA (miRNA) feed-forward loop (FFL) involving miR-23b-3p, CD44, and five transcription factors (TFs) [EOMES, FOS, FOSL1, GLIS3, TP63] specific to NSCLC metastasis. Further mutational analysis of these FFL elements revealed that all were altered in the patient samples analyzed. Thus, our study identified potential genomic drivers that may play crucial roles in NSCLC BM. Overall, it provides valuable insights for the discovery of novel therapeutic targets in the management of NSCLC metastasis. However, further in vitro and in vivo experimentations are needed to justify the prognostic role of NSCLC biomarkers in BM pathogenesis. Full article

Leaf senescence, the final developmental stage of a leaf, is a highly regulated process that is vital for the recycling of nutrients and the maintenance of plant fitness. Its control operates at multiple levels, including chromatin remodeling, transcription, post-transcriptional regulation, translation, and post-translational modifications. This review summarizes recent advances in understanding the roles of key transcription factor (TF) families—WRKY, NAC, and MYB—in modulating leaf senescence in Arabidopsis thaliana. We detail how these TFs integrate internal and external signals to regulate senescence-associated genes (SAGs). In addition, we explore the pivotal role of microRNAs (miRNAs) in post-transcriptional control of senescence, focusing on their regulation of these TF families. In conjunction with the transcriptome data of Arabidopsis miRNAs under conditions of dark-induced senescence, we also highlight several novel senescence-associated miRNAs. Integrating transcriptional and post-transcriptional perspectives, this review presents an updated regulatory network for leaf senescence and discusses potential applications for manipulating senescence in crops to improve yield and quality. Full article

Dysregulation of microRNA expression in breast cancer (BC) has been associated with molecular disturbances involved in cancer initiation, progression and metastasis. Specific microRNAs also act as endocrine modulators in BC, thereby influencing the biological behavior of the tumor and drug responses. Our objective was to employ bioinformatics tools to identify and characterize microRNAs acting as candidate players involved in epithelial–mesenchymal transition, migration, invasion, and/or hormonal regulation in BC. We systematically integrated microRNA profiling data from three different studies on BC cell lines with different invasive capabilities and from another study on lymph node metastases and matching primary BC, resulting in five microRNA hits—DE-microRNAs miR-146a-5p, miR-222-3p, miR-205-5p, miR-141-3p and miR-200c-3p. This set of microRNAs was evaluated for clinical significance in BC and subjected to target prediction, microRNA–mRNA network construction, functional enrichment analysis and quantification in BC cell lines by qPCR. An upregulated DE-microRNA, miR-222-3p, displayed distinctive pro-metastatic features, supported by its clinical relevance, as well as by the results of the functional enrichment analysis of its target genes. Downregulation of the members of the miR-200 family and miR-205-5p were significantly associated with negative clinical features, while their targets were enriched with genes that were relevant to cancer aggressiveness. These results are in line with the presumed functional relevance of the selected DE-microRNAs in BC. Full article

Chagas disease (CD) is a neglected tropical disease caused by the flagellate protozoan Trypanosoma cruzi, representing a major socioeconomic challenge. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression, and several pathogens, including T. cruzi, can modulate host miRNA networks. In this context, we hypothesized that host-derived miRNAs could serve as biomarkers in chronic CD. Given the intrinsic lability of RNA, we evaluated the efficacy of a 6 M guanidine-HCl/0.2 M EDTA solution, widely used in the molecular detection of T. cruzi DNA, in preserving mRNAs and miRNAs when mixed in a 1:1 ratio with human blood. Samples with or without guanidine were enriched with exogenous miRNAs (cel-miR-39 and cel-miR-54) and stored at 4 °C. RNase P expression was also evaluated in blood samples stored for up to 120 days and in samples from patients with CD, allowing direct comparison of mRNA stability over time. Samples preserved with guanidine-EDTA showed Ct values that were 4 to 5 cycles lower for all targets analyzed and demonstrated greater RNA stability over time. Taken together, these findings demonstrate that guanidine-EDTA robustly preserves mRNA and miRNAs in human blood, expanding the feasibility of molecular analyses in retrospective samples and corroborating its potential application in the studies of biomarkers of therapeutic response and prognosis in CD. Full article

Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and cellular homeostasis, and their dysregulation is now recognized as a hallmark of cancer. Over the past decades, extensive research has demonstrated that diverse ncRNA classes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other small ncRNA species, participate in complex regulatory networks that influence tumor initiation, progression, metastasis, and therapy response. Through mechanisms such as transcriptional regulation, post-transcriptional gene silencing, epigenetic modulation, and competitive endogenous RNA interactions, ncRNAs shape the molecular circuitry underlying cancer development. In addition to their functional roles in tumor biology, many ncRNAs are released into biological fluids and can be detected as circulating molecules in blood, urine, saliva, and other biofluids. Their remarkable stability in extracellular environments has generated considerable interest in their use as minimally invasive biomarkers in liquid biopsy applications. Emerging evidence has shown that circulating ncRNAs (c-ncRNAs) can support cancer detection, disease stratification, and treatment monitoring. This narrative review provides an integrated view that links ncRNA-mediated regulatory networks with their application as liquid biopsy biomarkers, positioning ncRNAs as comprehensive indicators of tumor conditions. Particular emphasis is placed on c-ncRNA biomarkers, the integration of multiple ncRNA classes, and multi-analyte biomarker strategies that combine ncRNAs with complementary circulating molecules such as cell-free DNA and protein markers. Finally, we discuss the technical and clinical challenges that currently limit the translation of ncRNA-based diagnostics into clinical practice and highlight future directions for advancing ncRNA-guided liquid biopsy approaches in precision oncology. Full article

Background: Aging is the strongest risk factor for prostate cancer (PCa). It is accompanied by progressive epigenomic divergence, known as epigenetic drift, particularly affecting DNA methylation at regulatory regions. However, the extent to which age-associated promoter methylation contributes to coordinated microRNA (miRNA) expression changes in PCa remains incompletely characterized. Methods: We conducted an integrative in silico analysis of 449 primary tumors from the TCGA-PRAD cohort. Age was modeled as a continuous variable. Age-related miRNA expression changes were estimated from miRNA-seq data using DESeq2. Promoter DNA methylation changes (±2 kb from transcription start sites) were assessed using Illumina 450K arrays and linear regression. MiRNAs showing significant age-associated alterations at both expression and methylation levels were classified as concordant or discordant based on directionality and prioritized using an effect size-based concordance score. We analyzed experimentally validated targets of prioritized miRNAs through functional enrichment and network-based approaches to identify convergent regulatory pathways. Results: Initially, we identified 105 age-associated miRNAs. After filtering, 65 candidates remained. Of these, we found 37 miRNAs with significant age-associated changes at both layers, including 20 concordant and 17 discordant miRNAs. These comprised well-characterized cancer-associated miRNAs and lesser-studied candidates enriched in CpG-rich regulatory regions. Network analyses revealed a limited set of genes under convergent regulation by multiple age-associated miRNAs. These implicated pathways are related to cell cycle control, apoptosis, stress response, and epigenetic regulation. Conclusions: Our findings support a model in which age-dependent promoter methylation drift contributes to coordinated miRNA deregulation in PCa. This convergence highlights biologically plausible miRNA biomarkers and age-sensitive epigenetic circuits relevant to prostate carcinogenesis. Full article

Colorectal cancer (CRC) persists as a significant public health burden due to its high morbidity and mortality rates worldwide, yet the molecular events that govern its initiation and progression remain incompletely understood. We recently conducted microRNA (miRNA) profiling and identified multiple dysregulated miRNAs in CRC compared to adjacent normal tissue. Among those, miR-138-5p emerged as a potential tumor suppressor due to its marked downregulation in CRC tissue; however, the stage-specific expression of this miRNA during CRC progression and underlying molecular mechanisms remains to be unraveled. In this study, we performed differential expression profiling of healthy colon, adenomatous polyp (AP), and CRC tissues based on public datasets, revealing significant downregulation of miR-138-5p in CRC compared to controls, but not during the AP stage, suggesting a role in later stages of malignant progression. Forced expression of miR-138-5p in HCT116 and HT-29 CRC models suppressed clonogenic survival, proliferation, and migration while inducing cell death. Additionally, miR-138-5p significantly inhibited tumor formation under three-dimensional culture settings, reinforcing its tumor-suppressive function in a physiologically relevant context. Transcriptomic profiling of miR-138-5p-overexpressing CRC models revealed widespread changes in the pathways related to zinc ion binding, cilium morphogenesis, smoothened signaling, and nuclear transport. Integrated computational and experimental analyses identified 41 potential gene targets, among which TCF3, UBE2C, EIF4EBP1, LYPLA1, and CD44 were validated as potential miR-138-5p-regulated genes. Collectively, these findings establish miR-138-5p as a stage-specific tumor suppressor in CRC, acting through coordinated regulation of oncogenic networks across multiple pathways. Downregulation of miR-138-5p appears to be a late oncogenic event, conferring proliferative, survival, and invasive advantages to tumor cells. Restoration of miR-138-5p or therapeutic targeting of its downstream effectors may represent promising avenues for CRC therapeutic intervention. Full article

Stanford type A aortic dissection (TAAD) is a life-threatening cardiovascular condition associated with high mortality. Ferroptosis has been implicated in TAAD pathogenesis, but comprehensive analyses and experimental validation of ferroptosis-related driver genes (FRDGs) remain limited. This study systematically investigated FRDGs in TAAD using bioinformatics and experimental approaches. Differentially expressed ferroptosis-related driver genes (DEFRDGs) were identified by integrating the GSE153434 dataset with the FerrDb database. Functional enrichment analysis was subsequently performed, followed by the construction of a protein–protein interaction (PPI) network, assessment of immune cell infiltration, and prediction of potential miRNA interactions. Candidate hub genes were then validated using an independent cohort (GSE52093) and clinical tissue samples, with their diagnostic value evaluated via receiver operating characteristic (ROC) curve analysis and their protein expression confirmed by immunohistochemistry. We identified 25 DEFRDGs (17 upregulated, 8 downregulated) enriched in oxidative stress, iron binding, and ferroptosis/HIF-1 signaling pathways. Six hub genes (HIF1A, IL6, TIMP1, SAT1, HMOX1, LPCAT3) were significantly upregulated in validation cohorts, five genes (HIF1A, TIMP1, SAT1, HMOX1, LPCAT3) achieved an area under the curve (AUC) of 1.000, while IL6 also exhibited high diagnostic accuracy (AUC = 0.914). Fibroblast infiltration was elevated in TAAD tissues. Further miRNA interaction prediction revealed the potential involvement of miRNAs, such as miR-138-5p, miR-18b-5p, miR-199a-5p, miR-185-5p, miR-506-3p and miR-4644. Immunohistochemistry confirmed increased protein expression of HIF1A, SAT1, and LPCAT3. These three genes emerge as key ferroptosis-related drivers in TAAD. Their consistent upregulation and strong diagnostic performance support ferroptosis as a potential therapeutic target and provide a basis for mechanism-focused interventions. Full article

Neuropathic pain represents a complex, prolonged pain state arising from lesions within the somatosensory nervous system. Despite significant advances in elucidating its pathophysiology, current therapeutic approaches remain largely symptomatic and frequently inadequate. MicroRNAs, a class of small non-coding RNAs that regulate gene expression post-transcriptionally, have recently emerged as critical modulators of neuronal excitability, neuroinflammation, and synaptic plasticity, which are crucial processes in the development and maintenance of neuropathic pain. This review summarizes the current evidence linking specific miRNAs to the onset and maintenance of neuropathic pain, with an emphasis on their roles in peripheral and central sensitization. The potential of miRNA-based biomarkers for diagnosis and prognostic evaluation is also highlighted. A thorough understanding of the complex miRNA regulatory networks underlying neuropathic pain could facilitate the development of novel, mechanism-based therapies and ultimately improve clinical outcomes. Full article