Osteosarcoma, the most prevalent malignant bone tumor in adolescents, is characterized by its aggressiveness and tendency to metastasize. Despite the advancements in treatment that have improved survival rates for localized cases, metastatic osteosarcoma remains challenging to treat due to the limited efficacy of current therapies and the severe side effects of chemotherapy. Epithelial-mesenchymal transition (EMT) is a key factor in osteosarcoma metastasis, and the miR-194/215 cluster, which is upregulated in osteosarcoma, promotes this process. This study sought to investigate natural compounds that could counteract the miR-194/215 cluster's effects and inhibit osteosarcoma metastasis. By analyzing miRNA databases and clinical data, a signature gene set for the miR-194/215 cluster was established, and the LINCS database was screened to find natural compounds with antagonistic effects. Icariside II, an active component of Epimedium, was identified as a potential inhibitor and was shown to reduce the migration and invasion of osteosarcoma cells in vitro and lung metastasis in vivo. The study utilized various techniques, including Gene Set Enrichment Analysis (GSEA), Drug Affinity Responsive Target Stability (DARTS), Cellular Thermal Shift Assay (CETSA), molecular docking, and enzyme activity assays, to identify phosphoglycerate kinase 1 (PGK1) as the target protein of Icariside II. It was found that Icariside II competitively inhibits PGK1 by binding to its ADP binding pocket, reducing its activity and thus antagonizing the miR-194/215 cluster's promotion of EMT in metastatic osteosarcoma. The results suggest that Icariside II could be a promising therapeutic agent for metastatic osteosarcoma, providing new targets and strategies for clinical treatment.

MicroRNAs (miRNAs) are short non‑coding RNAs, which perform a key role in cellular differentiation and development. Most human diseases, particularly cancer, are linked to miRNA functional dysregulation implicated in the expression of tumor‑suppressive or oncogenic targets. Cancer hallmarks such as continued proliferative signaling, dodging growth suppressors, invasion and metastasis, triggering angiogenesis, and avoiding cell death have all been demonstrated to be affected by dysregulated miRNAs. Thus, for the treatment of different cancer types, the detection and quantification of this type of RNA is significant. The classical and current methods of RNA detection, including northern blotting, reverse transcription‑quantitative PCR, rolling circle amplification and next‑generation sequencing, may be effective but differ in efficiency and accuracy. Furthermore, these approaches are expensive, and require special instrumentation and expertise. Thus, researchers are constantly looking for more innovative approaches for miRNA detection, which can be advantageous in all aspects. In this regard, an RNA manipulation tool known as the CRISPR and CRISPR‑associated sequence 13 (CRISPR/Cas13) system has been found to be more advantageous in miRNA detection. The Cas13‑based miRNA detection approach is cost effective and requires no special instrumentation or expertise. However, more research and validation are required to confirm the growing body of CRISPR/Cas13‑based research that has identified miRNAs as possible cancer biomarkers for diagnosis and prognosis, and as targets for treatment. In the present review, current updates regarding miRNA biogenesis, structural and functional aspects, and miRNA dysregulation during cancer are described. In addition, novel approaches using the CRISPR/Cas13 system as a next‑generation tool for miRNA detection are discussed. Furthermore, challenges and prospects of CRISPR/Cas13‑based miRNA detection approaches are described.

Type 2 diabetes mellitus (T2DM) and its complications, including diabetic lower extremity arterial disease (DLEAD) and diabetic foot (DF), impose significant health burdens worldwide. However, the differential expression of microRNAs (miRNAs) between T2DM and its complications and its causal effects remain poorly understood.

We conducted an exosome-wide association study (EWAS) comparing miRNA profiles between T2DM and its complications, including DLEAD and DF, without healthy controls. The significant miRNAs identified between DM and its complications were further validated by integrating cis-miRNA expression quantitative trait loci (cis-miR-eQTLs) and genome-wide association study (GWAS) summary data of T2DM and peripheral arterial disease (PAD) through two-sample Mendelian randomization (MR) analysis.

We identified several differential expressions of miRNAs between T2DM, DLEAD, and DF, such as hsa-miR-409-3p between T2DM and DLEAD, hsa-miR-543 between T2DM and DF and hsa-miR-206 between DLEAD and DF. The two sample MR analysis revealed potential causal relationships between dysregulated miRNAs and T2DM and its complications, such as hsa-miR-30b-3p and hsa-miR-30b-5p showed causal associations with T2DM and PAD respectively.

Our study elucidates the miRNA signatures associated with T2DM and its complications. These findings provide insights into the pathogenesis of T2DM and its complications and suggest potential therapeutic targets for intervention.

miRNA arm switching is a pivotal regulatory mechanism that allows organisms to fine-tune gene expression by selectively utilizing either the 5p or 3p strand of a miRNA duplex. This process, conserved across species, facilitates adaptive responses to developmental cues, environmental changes, and disease states. By dynamically altering strand selection, arm switching reshapes gene regulatory networks, contributing to phenotypic diversity and evolutionary innovation. Despite its growing recognition, the mechanisms driving arm switching-such as thermodynamic properties and enzyme-mediated processing-remain incompletely understood. This review synthesizes current findings, highlighting arm switching as a highly conserved mechanism with profound implications for the evolution of regulatory networks. We explore how this phenomenon expands miRNA functionality, drives phenotypic plasticity, and co-evolves with miRNA gene duplications to fuel the diversification of biological functions across taxa.

Growing evidence has identified potential biomarkers of cognitive-behavioural therapy (CBT) efficacy in obsessive-compulsive disorder (OCD). Genetic and epigenetic mechanisms (e.g., polymorphisms, DNA methylation) contribute to OCD pathogenesis and CBT response variability, establishing them as a key research focus. To evaluate their associations with CBT outcomes in OCD, we conducted a systematic review of PubMed, Web of Science, CNKI, and Cochrane Library (from inception to January 2025), identifying eight studies that met rigorous inclusion criteria. The identified predictors included: (1) Genetic polymorphisms (BDNF); (2) Epigenetic modifications (DNA methylation of MAOA, SLC6A4, OXTR, PIWIL1, MIR886, PLEKHA1, KCNQ1, TRPM8, HEBP1, HTR7P1, MAPK8IP3, ENAH, RABGGTB (SNORD45C), MYEF2, GALK2, CEP192, and UIMC1). These markers may influence neural plasticity, neurotransmitter regulation, and related processes, providing molecular substrates for the observed treatment effects. Converging evidence suggests that distinct neurocognitive mechanisms may mediate CBT efficacy in OCD, particularly fear extinction learning and goal-directed behaviors (GDBs), which we analyze mechanistically. Future studies should integrate polygenic risk scores (PRS) with functional neuroimaging to dissect individual variability in CBT response, mainly through cortico-striato-thalamo-cortical (CSTC) circuit profiling. To our knowledge, this is the first systematic review synthesizing genetic and epigenetic predictors of CBT response in OCD; these findings provide compelling evidence for biomarkers for CBT personalization in OCD, advancing a novel precision psychiatry framework.

Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities. Neuroinflammatory plaques formed through the extracellular deposition of amyloid-β proteins, as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins, comprise two typical pathological features of Alzheimer's disease. Besides symptomatic treatment, there are no effective therapies for delaying Alzheimer's disease progression. MicroRNAs (miR) are small, non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes. Indeed, miR-146a, a NF-κB-regulated gene, has been extensively implicated in the development of Alzheimer's disease through several pathways. Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder. MiR-146a is believed to reduce amyloid-β deposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway; however, there is also evidence supporting that it can promote these processes through many other pathways, thus exacerbating the pathological manifestations of Alzheimer's disease. It has been widely reported that miR-146a mediates synaptic dysfunction, mitochondrial dysfunction, and neuronal death by targeting mRNAs encoding synaptic-related proteins, mitochondrial-related proteins, and membrane proteins, as well as other mRNAs. Regarding the impact on glial cells, miR-146a also exhibits differential effects. On one hand, it causes widespread and sustained inflammation through certain pathways, while on the other hand, it can reverse the polarization of astrocytes and microglia, alleviate neuroinflammation, and promote oligodendrocyte progenitor cell differentiation, thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons. In this review, we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease. We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease, such as amyloid-β deposition, tau protein hyperphosphorylation, neuronal death, mitochondrial dysfunction, synaptic dysfunction, and glial cell dysfunction, as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.

Diverse CD4+ T cell subsets with specialized functions operate at different phases of the immune response. Among these are phenotypically and functionally characterized naïve, central memory (CM), effector memory (EM), and regulatory (Treg) cells. Using small RNA-sequencing, we have profiled miRNAs in these cell subsets from healthy subjects and untreated patients with relapsing-remitting multiple sclerosis (RRMS). MiRNA genomic clustering and abundance were also investigated. From the 60 most differentially expressed miRNAs, broad and highly selective core signatures were determined for naïve and memory cells at homeostasis, while miR-146a-5p was strongly upregulated in Treg cells. In line with other studies, a 5-miRNA core was identified for naïve cells (miR-125b-5p, miR-99a-5p, miR-365a-3p, miR-365b-3p, miR-193b-3p). In memory cells, a number of identical miRNAs were more expressed in EM than CM cells, supporting the progressive T cell differentiation model. This was particularly the case for an 8-miRNA core (members from miR-23a∼27a∼24-2, miR-23b∼27b∼24-1, miR-221∼222 clusters, miR-22-3p, miR-181c-5p) and for the large ChrXq27.3 miR-506∼514 cluster. Interestingly, most of these miRNAs were reported to negatively regulate cell proliferation and survival. Finally, we found that the miRNA core signatures of naïve and memory CD4+ T cells were conserved in RRMS patients. Only few miRNAs were quantitatively modified and, among these, miR-1248 was validated to be downregulated in EM cells. Overall, this study expands and provides novel insights into miRNA profiling of CD4+ T cell subsets that may be useful for further investigations.

Precise control of miRNA biogenesis is of extreme importance, since mis-regulation of miRNAs underlies or exacerbates many disease states. The Microprocessor complex, composed of DROSHA and DGCR8, carries out the first cleavage step in canonical miRNA biogenesis. Despite recent advances in understanding the molecular mechanism of Microprocessor, the N-terminal region of DROSHA is less characterized due its high intrinsic disorder. Here we demonstrate that Microprocessor forms condensates with properties consistent with liquid-liquid phase separation (LLPS) in select tissues in C. elegans . While DRSH-1/Drosha recruitment to granules is only partially dependent on its intrinsically disordered regions (IDRs), one of these N-terminal IDRs is crucial for biogenesis of a subset of miRNAs and normal development. A cis region of an IDR-dependent miRNA confers IDR-dependence to another miRNA, suggesting that the IDR recognizes sequences or structures in the miRNA primary transcript. Future studies will further elucidate the specificity of this interaction and the putative role of Microprocessor condensates.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic β-cells, leading to insulin deficiency. The primary drivers of β-cell destruction in T1D involve autoimmune-mediated processes that trigger chronic inflammation and ultimately β-cell loss. Regulatory microRNAs (miRNAs) play a crucial role in modulating these processes by regulating gene expression through post-transcriptional suppression of target mRNAs. Dysregulated miRNAs have been implicated in T1D pathogenesis, serving as both potential diagnostic biomarkers and therapeutic targets. This review explores the role of miRNAs in T1D, highlighting their involvement in disease mechanisms across both rodent models and human patients. While current antidiabetic therapies manage T1D symptoms, they do not prevent β-cell destruction, leaving patients reliant on lifelong insulin therapy. By summarizing key miRNA expression profiles in diabetic animal models and patients, this review explores the potential of miRNA-based therapies to restore β-cell function and halt or slow the progression of the disease.

Several microRNAs (miRNAs) have been identified as potential biomarkers widely dispersed in animals since 1993, and they have become a significant molecular biology research area. Because of their ability to activate extracellular molecules, stabilise bodily tissues, control cell-to-cell signals, and be easily extracted, miRNAs are outstandingly nominated as biomarkers. However, there is growing interest in targeting miRNAs to monitor physiological reproductive performance, including reproductive system development, embryo development, fertilisation, endocrinology, and animal welfare in stressful conditions. Moreover, miRNAs play significant roles in gene expression regulation; single miRNAs may have overlapping roles, and on a broader scale, multiple mRNAs govern a single function. Also, miRNAs serve as an intermediary messenger between the environment and reproductive performance, making them a vital component of miRNAs as performance biomarkers under environmental conditions like heat stress. This makes describing a unique miRNA's consequences and functions exceptionally challenging, which may confound many researchers. Also, enhancing our comprehension of miRNAs in response to testicular heat stress could potentially aid in preventing and treating spermatogenesis disorders. Therefore, the present review highlights miRNA's regulatory mechanisms on reproductive performance under heat stress to employ these findings in improving reproduction physiology research.

MicroRNAs (miRNAs) are small, yet profoundly influential, non-coding RNAs that base-pair with mRNAs to induce RNA silencing. Although the basic principles of miRNA biogenesis and function have been established, recent breakthroughs have yielded important new insights into the molecular mechanisms of miRNA biogenesis. In this Review, we discuss the metazoan miRNA biogenesis pathway step-by-step, focusing on the key biogenesis machinery, including the Drosha-DGCR8 complex (Microprocessor), exportin-5, Dicer and Argonaute. We also highlight newly identified cis-acting elements and their impact on miRNA maturation, informed by advanced high-throughput and structural studies, and discuss recently discovered mechanisms of clustered miRNA processing, target recognition and target-directed miRNA decay (TDMD). Lastly, we explore multiple regulatory layers of miRNA biogenesis, mediated by RNA-protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications.

MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.

MicroRNAs are essential regulators of gene expression. Their function is particularly important during neurogenesis, when the production of large numbers of neurons from a limited number of neural stem cells depends on the precise control of determination, proliferation and differentiation. However, microRNAs can target many mRNAs and vice-versa, raising the question of how specificity is achieved to elicit a precise regulatory response. Here we introduce in vivo AGO-APP, a novel approach to purify Argonaute-bound, and therefore active microRNAs from specific cell types. Using AGO-APP in the larval Drosophila central nervous system, we identify a module of microRNAs predicted to redundantly target all iconic genes known to control the transition from neuroblasts to neurons. While microRNA overexpression generally validated predictions, knockdown of individual microRNAs did not induce detectable phenotypes. In contrast, neuroblasts were induced to differentiate precociously when several microRNAs were knocked down simultaneously. Our data supports the concept that at physiological expression levels, the cooperative action of miRNAs allows efficient targeting of entire gene networks.

Vault RNA1-1 (vtRNA1-1) exhibits antiviral and anti-apoptotic effects in infected and malignant cells. We observed that vtRNA1-1 levels in serum fluctuate in patients with hematological disorders, but its extracellular functions remain unclear. This study evaluates the potential of serum vtRNA1-1 levels as a biomarker for hematological disorders and investigates its association with bone marrow cell density (BMC).

Blood and serum samples were collected from patients with hematological disorders, patients who underwent bone marrow examination, PBSCT donors, and AML patients who received chemotherapy. VtRNA1-1 levels were measured using real-time quantitative RT-PCR. BMC was calculated by digital image analysis, and multiple regression analysis was performed using serum vtRNA1-1 and hematological and biochemical data as explanatory variables.

The vtRNA1-1 levels in the blood of 11 patients with hematological disorders averaged 10.8 log10 cps/ml, significantly higher than 8.4 log10 cps/ml in serum. Multiple regression analysis estimated the vtRNA1-1 expression levels of each blood cell. In 87 patients who underwent bone marrow examination, there was a significant correlation between serum vtRNA1-1 levels and BMC (Rs = 0.24, P = 0.023). In PBSCT donors, serum vtRNA1-1 levels increased after G-CSF administration (P < 0.001), and in AML patients, serum vtRNA1-1 levels decreased after the initiation of chemotherapy, fluctuating in parallel with white blood cell counts.

Our findings suggest that serum vtRNA1-1, derived from peripheral blood and bone marrow cells, can potentially serve as a clinical biomarker in specific diseases.

MicroRNAs (miRNAs) are a class of non-coding RNA sequences that regulate gene expression post-transcriptionally. The miR-99 family, which is highly evolutionarily conserved, comprises three homologs: miR-99a, miR-99b, and miR-100. Its members are under-expressed in most cancerous tissues, suggesting their cancer-repressing properties in multiple cancers; however, in some contexts, they also promote malignant lesion progression. MiR-99 family members target numerous genes involved in various tumor-related processes such as tumorigenesis, proliferation, cell-cycle regulation, apoptosis, invasion, and metastasis. We review the recent research on this family, summarize its implications in cancer, and explore its potential as a biomarker and cancer therapeutic target. This review contributes to the clinical translation of the miR-99 family members.

MicroRNAs (miRNAs) are ~22-nucleotide small non-coding RNAs that play critical roles in gene regulation. The discovery of miRNAs in Caenorhabditis elegans in 1993 by the research groups of Victor Ambros and Gary Ruvkun opened a new era in RNA research. Typically, miRNAs act as negative regulators of gene expression by binding to complementary sequences within the 3' untranslated regions of their target mRNAs. This interaction results in translational repression and/or target destabilization. The expression levels and activities of miRNAs are fine-tuned by multiple factors, including the miRNA biogenesis pathway, variability in target recognition, super-enhancers, post-transcriptional modifications, and target-directed miRNA degradation. Together, these factors form complex mechanisms that govern gene regulation and underlie several pathological conditions, including Argonaute syndrome, genetic diseases driven by super-enhancer-associated miRNAs, and miRNA-deadenylation-associated bone marrow failure syndromes. In addition, as miRNA genes have evolved rapidly in vertebrates, miRNA regulation in the brain is characterized by several unique features. In this review, we summarize recent insights into the role of miRNAs in human diseases, focusing on miRNA biogenesis; regulatory mechanisms, such as super-enhancers; and the impact of post-transcriptional modifications. By exploring these mechanisms, we highlight the intricate and multifaceted roles of miRNAs in health and disease.

Transposable element (TE) expansion has long been known to mediate genome evolution and phenotypic diversity in organisms, but its impact on the evolution of post-transcriptional regulation following species divergence remains unclear.

To address this issue, we perform long-read direct RNA sequencing, polysome profiling sequencing, and small RNA sequencing in the cotton genus Gossypium, the species of which range more than three folds in genome size. We find that TE expansion contributes to the turnover of transcription splicing sites and regulatory sequences, leading to changes in alternative splicing patterns and the expression levels of orthologous genes. We also find that TE-derived upstream open reading frames and microRNAs serve as regulatory elements mediating differences in the translation levels of orthologous genes. We further identify genes that exhibit lineage-specific divergence at the transcriptional, splicing, and translational levels, and showcase the high flexibility of gene expression regulation in the evolutionary process.

Our work highlights the significant role of TE in driving post-transcriptional regulation divergence in the cotton genus. It offers insights for deciphering the evolutionary mechanisms of cotton species and the formation of biological diversity.

Silencing by the miRNA-guided RNA induced silencing complex (miRISC) is dependent on Ago2-chaperoned base pairing between the miRNA 5' seed (5'S) and a complementary sequence in the 3' untranslated region of an mRNA. Prevailing mechanistic understanding posits that initial 5'S pairing can further allow functional base pair expansion into the 3' non-seed (3'NS), while functionally distinct non-canonical pairing was reported between only the 3'NS and the mRNA coding sequence. We developed single-molecule kinetics through equilibrium Poisson sampling (SiMKEPS) to measure highly precise binding and dissociation rate constants of varying-length target sequences to 5'S and 3'NS in a paradigmatic miRISC isolated from human cells, revealing distinct stable states of miRISC with mutually exclusive 5'S and 3'NS pairing. Our data suggest conformational rearrangements of the Ago2-bound miRNA that regulate alternative 5'S- and 3'NS-driven target recognition. The resulting model reconciles previously disparate observations and deepens our acumen for successfully marshaling RNA silencing therapies.

miRNAs are small noncoding elements known to regulate different molecular processes, including developmental and executive functions in the brain. Dysregulation of miRNAs could contribute to brain neurodegeneration, as suggested by miRNA profiling studies of individuals suffering from neurodegenerative brain diseases (NBDs). Here, we report rare miRNA variants in patients with Alzheimer's dementia (AD) and frontotemporal dementia (FTD).

We initially used whole exome sequencing data in a subset of FTD patients (n = 209) from Flanders-Belgium. We then performed targeted resequencing of variant-harboring miRNAs in an additional subset of FTD patients (n = 126) and control individuals (n = 426). Lastly, we sequenced the MIR885 locus in a Flanders-Belgian AD cohort (n = 947) and a total number of n = 755 controls.

WES identified rare seed variants in MIR656, MIR423, MIR122 and MIR885 in FTD patients. Most of these miRNAs bind to FTD-associated genes, implicated in different biological pathways. Additionally, some miRNA variants create novel binding sites for genes associated with FTD. Sequencing of the MIR885 locus in the AD cohort initially showed a significant enrichment of MIR885 variants in AD patients compared to controls (SKAT-O, p-value = 0.026). Genetic association was not maintained when we included sex and APOE status as covariates. Using the miRVaS prediction tool, variants rs897551430 and rs993255773 appeared to evoke significant structural changes in the primary miRNA. These variants are also predicted to strongly downregulate mature miR885 levels, in line with what is reported for MIR885 in the context of AD.

Functional investigation of miRNAs/variants described in this study could propose novel miRNA-mediated molecular cascades in FTD and AD pathogenicity. Furthermore, we believe that the genetic evidence presented here suggests a role for MIR885 in molecular mechanisms involved in AD and warrants genetic follow-up in larger cohorts to explore this hypothesis.

In animals, a trade-off exists between reproduction and growth, which are the most fundamental traits. Males and females exhibit profound differences in reproduction and growth in fish species. However, the precise molecular mechanism governing this phenomenon is still not clear. Here, we uncovered that chr23-miR-200s and dmrt1 knockout specifically caused an impairment in reproduction and an increase in body growth in female and male zebrafish, respectively. Chr23-miR-200s and Dmrt1 directly regulate the stat5b gene by targeting its 3'UTR and promoter. The loss of stat5b completely abolished the elevated growth performance in chr23-miR-200s-KO or dmrt1-/- zebrafish. Moreover, the dmrt1 transgenic zebrafish had significantly lower body length and body weight than the control males, accompanied by a significant reduction in stat5b expression in the liver of transgenic fish. In summary, our study proposes a regulatory model elucidating the roles of chr23-miR-200s and Dmrt1 in controlling the sexually dimorphic trade-off between reproduction and growth.

The purpose of this review is to explore the multifaceted roles of the ERI1 exoribonuclease, particularly in RNA metabolism and bone development, and to address the genotype-phenotype complexity in patients and mice with ERI1 pathogenic variants.

The 3'-to-5' exoribonuclease 1 encoded by the ERI1 gene performs a variety of biologically essential functions, including modulating RNA interference, heterochromatin formation, rRNA maturation, and histone mRNA degradation. Recently, the relationship between ERI1 variants and human skeletal dysplasia has garnered increasing attention. In a phenotypic dichotomy associated with bi-allelic ERI1 variants, patients with at least one missense pathogenic variant exhibited severe spondylo-epi-metaphyseal dysplasia (SEMD), while those with bi-allelic nonsense pathogenic variant only presented mild anomaly in digits. The biological mechanisms underlying the bone dysplasia caused by ERI1 pathogenic variants remain unknown. Although Eri1 knockout (KO) mice showed mild skeletal phenotypes, neither SEMD nor digital anomaly were found, further underscoring a complex genotype-phenotype relationship of ERI1 pathogenic variants. We systematically reviewed the advances in exploring the multiple functions of ERI1 with emphasis on its roles in RNA metabolism and skeletal development. Our review would contribute to the understanding of the phenotypic spectrum caused by ERI1 pathogenic variants and the limitations of existing disease models in revealing the corresponding pathomechanism.

Early and personalized intervention in complex diseases requires robust molecular diagnostics, yet the simultaneous detection of diverse biomarkers-microRNAs (miRNAs), mutant DNAs, and proteins-remains challenging due to low abundance and preprocessing incompatibilities. We present Biomarker Single-molecule Chromato-kinetic multi-Omics Profiling and Enumeration (Bio-SCOPE), a next-generation, triple-modality, multiplexed detection platform that integrates both chromatic and kinetic fingerprinting for molecular profiling through digital encoding. Bio-SCOPE achieves femtomolar sensitivity, single-base mismatch specificity, and minimal matrix interference, enabling precise, parallel quantification of up to six biomarkers in a single sample with single-molecule resolution. We demonstrate its versatility in accurately detecting low-abundance miRNA signatures from human tissues, identifying upregulated miRNAs in the plasma of prostate cancer patients, and measuring elevated interleukin-6 (IL-6) and hsa-miR-21 levels in cytokine release syndrome patients. By seamlessly integrating multiomic biomarker panels on a unified, high-precision platform, Bio-SCOPE provides a transformative tool for molecular diagnostics and precision medicine.

Neonatal mammals must rapidly adapt to significant physiological changes during the transition from the intrauterine to extrauterine environments. This adaptation, particularly in the metabolic and respiratory systems, is essential for survival. MicroRNAs (miRNAs) are small noncoding RNAs that regulate various physiological and pathological processes by binding to the 3' untranslated regions of mRNAs. This study aimed to identify miRNAs involved in the early extrauterine adaptation of neonatal piglets and explore their functions. We performed small RNA sequencing on six tissues (heart, liver, spleen, lung, multifidus muscle, and duodenum) from piglets 24 h before birth (day 113 of gestation) and 6 h after birth. A total of 971 miRNA precursors and 1511 mature miRNAs were identified. Tissue-specific expression analysis revealed 881 tissue-specific miRNAs and 164 differentially expressed miRNAs (DE miRNAs) across the tissues. Functional enrichment analysis showed that these DE miRNAs are significantly enriched in pathways related to early extrauterine adaptation, such as the NFκB, PI3K/AKT, and Hippo pathways. Specifically, miR-22-3p was significantly upregulated in the liver post-birth and may regulate the PI3K/AKT pathway by targeting AKT3, promoting gluconeogenesis, and maintaining glucose homeostasis. Dual-luciferase reporter assays and HepG2 cell experiments confirmed AKT3 as a target of miR-22-3p, which activates the AKT/FoxO1 pathway, enhancing gluconeogenesis and glucose production. Furthermore, changes in blood glucose and liver glycogen levels in newborn piglets further support the role of miR-22-3p in glucose homeostasis. This study highlights the importance of miRNAs, particularly miR-22-3p, in the early extrauterine adaptation of neonatal piglets, offering new insights into the physiological adaptation of neonatal mammals.

Rheumatoid arthritis (RA) is a progressive systemic autoimmune disease characterized by chronic inflammation of synovial joints and impaired immunological tolerance. It ultimately results in irreversible joint degeneration. This study aimed to measure Cell-Free DNA (cf-DNA), miR-21, and miR-146a and assess their disease activity levels in RA.

This case-control trial was conducted on 80 subjects (patients and control groups). Cases were categorised into two groups: Group I: 20 cases with active disease and Group II: 20 cases with inactive disease. Group III (control): 40 healthy subjects with matched age and sex. The DAS-28 score was used to assess the RA disease activity. This study demonstrated that miRNA21, miRNA 146a, and cf-DNA significantly increased in both active and inactive groups compared to controls (P-value < 0.001). In addition, there was a significant increase in the active group compared to the inactive group (P-value < 0.001). In the active group, miRNA 146a and cf-DNA exhibited a significant positive correlation with the DAS-28 score and clinical manifestations, including morning stiffness, joint tenderness, and swelling. The linear regression analysis revealed that the primary predictors of miRNA21, miRNA 146a, and cf-DNA levels are the DAS-28 score, ESR, and disease duration.

miRNA 146a can be considered a valuable marker for disease activity in RA patients. Furthermore, cf-DNA is suggested to indicate inflammatory conditions; however, MiR21 did not show a significant association with disease activity.

Research on epigenetic‒environmental interactions in the development of Alzheimer's disease (AD) has accelerated rapidly in recent decades. Numerous studies have demonstrated the contribution of ambient particulate matter (PM) to the onset of AD. Emerging evidence indicates that non-coding RNAs (ncRNAs), including long non-coding RNAs, circular RNAs, and microRNAs, play a role in the pathophysiology of AD. In this review, we provide an overview of PM-altered ncRNAs in the brain, with emphasis on their potential roles in the pathogenesis of AD. These results suggest that these PM-altered ncRNAs are involved in the regulation of amyloid-beta pathology, microtubule-associated protein Tau pathology, synaptic dysfunction, damage to the blood‒brain barrier, microglial dysfunction, dysmyelination, and neuronal loss. In addition, we utilized in silico analysis to explore the biological functions of PM-altered ncRNAs in the development of AD. This review summarizes the knowns and unknowns of PM-altered ncRNAs in AD pathogenesis and discusses the current dilemma regarding PM-altered ncRNAs as promising biomarkers of AD. Altogether, this is the first thorough review of the connection between PM exposure and ncRNAs in AD pathogenesis, which may offer novel insights into the prevention, diagnosis, and treatment of AD associated with ambient PM exposure.

The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142-/- mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer's patches. Conditional deletion of Mir142 in ILC3s (RorcΔMir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.

Breast cancer is the leading cause of cancer-related mortality in women. Deregulation of miRNAs is frequently observed in breast cancer and affects tumor biology. A pre-miRNA, such as pre-miR-1307, gives rise to several mature miRNA molecules with distinct functions. However, the impact of global deregulation of pre-miR-1307 and its individual mature miRNAs in breast cancer has not been investigated in breast cancer, yet.

Here, we found significant upregulation of three mature miRNA species derived from pre-miR-1307 in human breast cancer tissue. Surprisingly, the overexpression of pre-miR-1307 in breast cancer cell lines resulted in reduced xenograft growth and impaired angiogenesis. Mechanistically, overexpression of miR-1307-5p altered the secretome of breast cancer cells and reduced endothelial cell sprouting. Consistently, expression of miR-1307-5p was inversely correlated with endothelial cell fractions in human breast tumors pointing at an anti-angiogenic role of miR-1307-5p. Importantly, the arm usage of miR-1307 and other miRNAs was highly correlated, which suggests an undefined common regulatory mechanism.

In summary, miR-1307-5p reduces angiogenesis in breast cancer, thereby antagonizing the oncogenic effects of miR-1307-3p. Our results emphasize the importance of future research on the regulation of miRNA arm selection in cancer. The underlying mechanisms might inspire new therapeutic strategies aimed at shifting the balance towards tumor-suppressive miRNA species.

Primary liver cancer (PLC) is one of the most common cancers worldwide. ABO blood groups and rhesus (Rh) factor are inherited characteristics. Their association with the presence of PLC remains unclear in cirrhotic patients. Hence, the purpose of this cross-sectional study was to evaluate whether blood groups were risk factors for the presence of PLC in cirrhosis.

Patients with liver cirrhosis who were consecutively admitted to the Department of Gastroenterology of the General Hospital of Northern Theater Command from 1 January 2010 to 30 June 2014 were retrospectively screened. Logistic regression analyses were performed to explore the association of ABO blood groups and Rh factor with PLC in cirrhotic patients. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated after adjusting for gender, age, family history of liver cirrhosis, HBV-DNA positivity, and etiology of cirrhosis. Subgroup analyses were performed according to the etiology of liver cirrhosis.

Overall, 1,158 cirrhotic patients without PLC and 240 cirrhotic patients with PLC were included in the study. After adjusting for confounding factors, non-O (aOR = 0.763; 95%CI = 0.449-1.298, p = 0.319), A (aOR = 0.643; 95%CI = 0.332-1.246, p = 0.191), B (aOR = 0.835; 95%CI = 0.453-1.540, p = 0.564), AB (aOR = 0.888; 95%CI = 0.363-2.170, p = 0.795), and Rh (+) (aOR = 0.239; 95%CI = 0.036-1.571, p = 0.136) blood groups were not independently associated with PLC in cirrhotic patients. In the subgroup analysis of HBV-related cirrhotic patients, the proportion of A blood group was significantly lower in cirrhotic patients with PLC than in those without PLC (24.17% vs. 33.99%, p < 0.001); however, in HCV- and alcohol-related cirrhotic patients, the proportions of ABO blood groups and Rh factor were not significantly different between the two groups.

ABO blood groups and Rh factor may not be associated with the presence of PLC in cirrhotic patients.

Despite tremendous advances in antiretroviral therapy (ART) against HIV-1 infections, no cure or vaccination is available. Therefore, discovering novel therapeutic strategies remains an urgent need. In that sense, miRNAs and miRNA therapeutics have moved intensively into the focus of recent HIV-1-related investigations. A strong reciprocal interdependence has been demonstrated between HIV-1 infection and changes of the intrinsic cellular miRNA milieu. This interrelationship may direct potential alterations of the host cells' environment beneficial for the virus or its suppression of replication. Whether this tightly balanced and controlled battle can be exploited therapeutically remains to be further addressed. In this context, the fluoroquinolone antibiotic Enoxacin has been demonstrated as a potent modulator of miRNA processing. Here, we test the hypothesis that this applies also to selected HIV-1-related miRNAs.

We studied the effect of Enoxacin on HIV-1 replication coupled with miRNA qRT-PCR analysis of HIV-1-related miRNAs in CEM-SS and MT-4 T-cells. The effects of miRNA mimic transfections combined with Enoxacin treatment on HIV-1 replication were assessed. Finally, we employed an in vitro DICER1 cleavage assay to study the effects of Enoxacin on a pro-HIV-1 miRNA hsa-miR-132 processing.

We established that Enoxacin, but not the structurally similar compound nalidixic acid, exhibits strong anti-HIV-1 effects in the T-cell line CEM-SS, but not MT-4. We provide experimental data that this effect of Enoxacin is partly attributed to the specific downregulation of mature hsa-miR-132-3p, but not other tested pro- or anti-HIV-1 miRNAs, which is likely due to affecting DICER1 processing.

Our findings show an anti-retroviral activity of Enoxacin at least in part by downregulation of hsa-miR-132-3p, which may be relevant for future antiviral therapeutic applications by modulation of the RNA interference pathway.

Over the past two decades, the study of sperm-borne small non-coding RNAs (sncRNAs) has garnered substantial growth. Once considered mere byproducts during germ cell maturation, these sncRNAs have now been recognized as crucial carriers of epigenetic information, playing a significant role in transmitting acquired traits from paternal to offspring, particularly under environmental influences. A growing body of evidence highlights the pivotal role of these sncRNAs in facilitating epigenetic inheritance across generations. However, the exact mechanisms through which these paternally supplied epigenetic carriers operate remain unclear and are under hot debate. This concise review presents the most extensive evidence to date on environmentally-responsive sperm-borne sncRNAs, encompassing brief summary of their origin, dynamics, compartmentalization, characteristics, as well as in-depth elaboration of their functional roles in epigenetic and transgenerational inheritance. Additionally, the review delves into the potential mechanisms by which sperm-delivered sncRNAs may acquire and transmit paternally acquired traits to offspring, modulating zygotic gene expression and influencing early embryonic development.

The simultaneous sequencing of multiple types of biomolecules can facilitate understanding various forms of regulation occurring in cells. Cosequencing of miRNA and mRNA at single-cell resolution is challenging, and to date, only a few such studies (examining a quite limited number of cells) have been reported. Here, we developed a parallel single-cell small RNA and mRNA coprofiling method (PSCSR-seq V2) that enables miRNA and mRNA coexpression analysis in many cells. The PSCSR-seq V2 method is highly sensitive for miRNA analysis, and it also provides rich mRNA information about the examined cells at the same time. We employed PSCSR-seq V2 to profile miRNA and mRNA in 2310 cultured cells, and detected an average of 181 miRNA species and 7354 mRNA species per cell. An integrated analysis of miRNA and mRNA profiles linked miRNA functions with the negative regulation of tumor suppressor and reprogramming of cellular metabolism. We coprofiled miRNA and mRNA in 9403 lung cells and generated a coexpression atlas for known cell populations in mouse lungs, and detected conserved expression patterns of miRNAs among lineage-related cells. Based on this information, we identified informative age-associated miRNAs in mouse and human lung cells including miR-29, which can be understood as a conserved marker for immunosenescence. PSCSR-seq V2 offers unique functionality to users conducting functional studies of miRNAs in clinical and basic biological research.

Hepatocellular carcinoma (HCC) has been a pervasive malignancy throughout the world with elevated mortality. Efficient therapeutic targets are beneficial to treat and predict the disease. Currently, the exact molecular mechanisms leading to the progression of HCC are still unclear. Research has shown that the microRNA-142-3p level decreases in HCC, whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues. In this paper, we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity, and the association between them.

To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.

In this study, we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues, and retrospectively analyzed the prognosis of HCC patients. Furthermore, explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments, which involved the following experimental methods: Immunohistochemical staining, western blot, quantitative real-time-polymerase chain reaction, flow cytometric analysis, tumor xenografts in nude mice, etc. The statistical methods involved in this study contained t-test, one-way analysis of variance, the χ 2 test, the Kaplan-Meier approach and the log-rank test.

In this study, we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate. ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3'untranslated region. Furthermore, microRNA-142-3p promotes apoptosis and inhibits proliferation, invasion, and migration of HCC cell lines in vitro via ASH1L. For the exploration mechanism, we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1, which is potentially relevant to the immune system.

Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC. Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.

MiRNAs represent a non-coding RNA class that regulate gene expression and pathways. While miRNAs are evolutionary conserved most data stems from Homo sapiens and Mus musculus. As miRNA expression is highly tissue specific, we developed miRNATissueAtlas to comprehensively explore this landscape in H. sapiens. We expanded the H. sapiens tissue repertoire and included M. musculus. In past years, the number of public miRNA expression datasets has grown substantially. Our previous releases of the miRNATissueAtlas represent a great framework for a uniformly pre-processed and label-harmonized resource containing information on these datasets. We incorporate the respective data in the newest release, miRNATissueAtlas 2025, which contains expressions from 9 classes of ncRNA from 799 billion reads across 61 593 samples for H. sapiens and M. musculus. The number of organs and tissues has increased from 28 and 54 to 74 and 373, respectively. This number includes physiological tissues, cell lines and extracellular vesicles. New tissue specificity index calculations build atop the knowledge of previous iterations. Calculations from cell lines enable comparison with physiological tissues, providing a valuable resource for translational research. Finally, between H. sapiens and M. musculus, 35 organs overlap, allowing cross-species comparisons. The updated miRNATissueAtlas 2025 is available at https://www.ccb.uni-saarland.de/tissueatlas2025.

Brain-derived neurotrophic factor (BDNF) is essential for the development and functioning of the vestibular system. BDNF promotes the growth, differentiation, and synaptic plasticity of vestibular neurons, ensuring their normal operation and maintenance. According to research, BDNF is pivotal during vestibular compensation, aiding in the recovery of neuron function by remodeling the spontaneous resting potentials of damaged vestibular neurons. Additionally, BDNF exhibits dose-dependent and age-dependent characteristics during vestibular system development, with its deficiencies leading to the degeneration of vestibular neurons. BDNF dynamically interacts with other neurotrophic factors, such as fibroblast growth factor-2 (FGF-2) and glial cell line-derived neurotrophic factor (GDNF), synergistically enhancing neuron survival and functionality. This review outline the function of BDNF in the vestibulocochlear system and explores its potential therapeutic applications, offering fresh perspectives and guidance for future research and treatment of vestibulocochlear system disorders.

Male-typical behaviors such as aggression and mating, which reflect sexual libido in male mice, are regulated by the hypothalamus, a crucial part of the nervous system. Previous studies have demonstrated that microRNAs (miRNAs), especially miR-29, play a vital role in reproduction and the neural control of behaviors. However, it remains unclear whether miR-29 affects reproduction through the hypothalamus-mediated regulation of male-typical behaviors. Here, we constructed two mouse knockout models by ablating either the miR-29ab1 or miR-29b2c cluster. Compared to WT, the ablation of miR-29ab1 in male mice significantly reduced the incidence of aggression by 60% and the incidence of mating by 46.15%. Furthermore, the loss of miR-29ab1 in male mice led to the downregulation of androgen receptor (AR) in the ventromedial hypothalamus. Transcriptomic analysis of the hypothalamus of miR-29ab1-deficient mice revealed inflammatory activation and aberrant expression of genes associated with male-typical behaviors, including Ar, Pgr, Htr4, and Htr2c. Using bioinformatics analysis and dual-luciferase reporter assays, we identified zinc finger protein 36 (Zfp36) as a direct downstream target gene of miR-29ab1. We subsequently showed that ZFP36 colocalized with AR in GT1-7 cells. Furthermore, inhibition of Zfp36 or RelB in GT1-7 cells led to an increase in AR expression. Collectively, our results demonstrate that the miR-29ab1/Zfp36/AR axis in the hypothalamus plays a pivotal role in the regulation of aggression and mating in male mice, providing a potential therapeutic target for treating infertility caused by low libido.

Non-coding 886 (nc886, vtRNA2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNA(s) has been redefined multiple times, and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of the nc886 locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets. Herein, we aim to summarize the existing literature regarding nc886, discuss how the characteristics of nc886 give rise to contradictory results, as well as to reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how the distribution of the nc886 methylation pattern is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.

Precisely sensing and guiding cell-state transitions via the conditional genetic activation of appropriate differentiation factors is challenging. Here we show that desired cell-state transitions can be guided via genetically encoded sensors, whereby endogenous cell-state-specific miRNAs regulate the translation of a constitutively transcribed endoribonuclease, which, in turn, controls the translation of a gene of interest. We used this approach to monitor several cell-state transitions, to enrich specific cell types and to automatically guide the multistep differentiation of human induced pluripotent stem cells towards a haematopoietic lineage via endothelial cells as an intermediate state. Such conditional activation of gene expression is durable and resistant to epigenetic silencing and could facilitate the monitoring of cell-state transitions in physiological and pathological conditions and eventually the 'rewiring' of cell-state transitions for applications in organoid-based disease modelling, cellular therapies and regenerative medicine.

Lupus nephritis (LN) is the most severe end-organ pathology in Systemic Lupus Erythematosus (SLE). Research has enhanced our understanding of immune effectors and inflammatory pathways in LN. However, even with the best available therapy, the rate of complete remission for proliferative LN remains below 50%. A deeper understanding of the resistance or susceptibility of renal cells to injury during the progression of SLE is critical for identifying new targets and developing effective long-term therapies. The complex and heterogeneous nature of LN, combined with the limitations of clinical research, make it challenging to investigate the aetiology of this disease directly in patients. Hence, multiple murine models resembling SLE-driven nephritis are utilised to dissect LN's cellular and genetic mechanisms, identify therapeutic targets, and screen novel compounds. This review discusses commonly used spontaneous and inducible mouse models that have provided insights into pathogenic mechanisms and long-term maintenance therapies in LN.