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PubMed2025

Constructing epigenetic regulatory landscapes of plant lncRNAs-an exploration utilizing the novel specialized platform PERlncDB.

Long non-coding RNAs (lncRNAs), once overlooked as transcriptional byproducts, are now recognized for their crucial roles in plant growth, development, and stress responses, with increasing focus on their epigenetic regulation. However, studies investigating epigenomic signals to explore the functions of lncRNAs in plants remain relatively limited. This study collected a comprehensive dataset of over 160 000 high-quality lncRNAs from 19 representative plant species and integrated 6715 ChIP-seq, BS-seq, and RNA-seq datasets to analyze epigenomic patterns at lncRNA loci. Results showed elevated DNA methylation in lncRNA regions. The highest levels occurred in transposable element-associated lncRNAs. Additionally, activating histone modifications at lncRNA loci showed tissue specificity, with epigenetic preferences differed from those at protein-coding gene (PCG) loci. Differential site analysis in epigenetic mutants further highlighted the selective regulation of lncRNA loci by specific epigenetic factors. To facilitate research, we developed PERlncDB, a platform that provides species-specific lncRNA browsing, epigenetic annotation, cross-species conservation analysis, and visualization of epigenomic landscapes. Case studies on MARS and LINC-AP2 emphasized the platform's utility. Conserved epigenetic mechanisms regulating lncRNAs across species, exemplified by a syntenic conserved MET1-regulated lncRNA pair in Arabidopsis and tomato, suggested the stability of regulatory mechanisms underlying lncRNA functions. This work provides critical insights and resources for understanding plant lncRNA epigenetic regulation.

RNA, Long Noncoding↗

PubMed2026

How advances in machine learning drive early detection and risk prediction of early-onset colorectal cancer.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before age 50, is rising across high- and middle-income settings whilst organised screening stays anchored to older age thresholds. Blood-based liquid biopsy, combined with machine learning, is the most plausible route to early detection in this group because it does not depend on bowel preparation, endoscopy capacity, or adherence to stool-based testing. The gap is structural: incidence climbs fastest in the population below the age at which any guideline-endorsed modality is offered. The analytical challenge is that early-stage tumour-derived signals in plasma are low in abundance and distributed across heterogeneous molecular layers: circulating tumour DNA mutations, aberrant methylation, cfDNA fragmentomics, and small non-coding RNA. Machine learning converts these into a single calibrated probability. This review examines where artificial intelligence (AI)-driven liquid biopsy genuinely adds diagnostic value in EOCRC, distinguishes components in which learned models are decorative from those in which they are mechanistically necessary, and identifies the validation deficit separating research cohorts from deployable clinical tools. It summarises the first-generation tools used clinically for early detection and post-treatment monitoring, then considers analytes from exosome-bound microRNAs to long-read whole-genome sequencing of circulating plasma DNA, which reads cytosine modification natively, resolves methylation and fragmentation on single molecules, and characterises structural events short reads cannot anchor. Any analyte can feed a learned model, but more diverse input yields better discrimination. The central argument is that approved, guideline-included blood tests were validated in populations aged 45 and above, and their performance in younger patients cannot be assumed.

cfDNA fragmentomics↗

PubMed2025

Genome-Wide Mining of lncRNAs Reveals Their Potential Regulatory Role in the Evolution of Viviparity.

Reproduction in vertebrates usually involves egg-laying (oviparity) or live-bearing (viviparity). Oviparity is the ancestral trait from which viviparity has independently evolved more than 100 times in squamate reptiles. This transition involves a series of physiological and structural changes, including the degeneration of eggshell and the evolution of a placenta and differences in the temporal and spatial expression patterns of some functional genes that drive the structural transformation. Long non-coding RNAs (lncRNAs) play important roles in the regulation of gene expression, yet it remains unclear whether they participate in gene expression shifts during the transition from oviparity to viviparity, and if so how. Therefore, we employ deep mining to identify novel lncRNAs of a closely related oviparous-viviparous pair of lizards (Phrynocephalus przewalskii and P. vlangalii). We construct cis- and trans-regulatory networks between lncRNAs and target genes using the transcriptomic data of oviduct or uteri tissues across reproductive periods. Results show that lncRNAs that regulate eggshell gland developmental genes in the oviparous lizard are lost or less expressed in the viviparous lizard. A number of lncRNAs involved in the regulation of placental development and embryo attachment in viviparous species have no orthologs in oviparous species, and others show little or no expression. Accordingly, lncRNAs may play important regulatory roles in the physiological and structural changes in the transition from oviparity to viviparity. These results open doors to the further elucidation of genetic regulatory networks.

Animals↗

PubMed2026

LncRNA DNAJC3-AS1 promotes gastric cancer malignancy through miR-576-5p-mediated upregulation of LYPLA1.

Long non-coding RNAs (lncRNAs) are involved in tumor progression, but the role of lnc-DNAJC3-AS1 in gastric cancer (GC) remains unclear. This study aimed to investigate the biological function and regulatory mechanism of lnc-DNAJC3-AS1 in GC. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression levels of lnc-DNAJC3-AS1, miR-576-5p, and LYPLA1, and Western blot was used to analyze protein expression. The Cancer Genome Atlas (TCGA) database and clinical samples were used to evaluate their clinical relevance. Cell viability, cell cycle distribution, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing, Transwell, and immunofluorescence assays. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and rescue assays were performed to explore the potential regulatory relationship among lnc-DNAJC3-AS1, miR-576-5p, and LYPLA1. A xenograft tumor model was also established to evaluate the role of lnc-DNAJC3-AS1 in vivo. The results showed that lnc-DNAJC3-AS1 and LYPLA1 were upregulated, whereas miR-576-5p was downregulated in GC tissues and cells. Knockdown of lnc-DNAJC3-AS1 inhibited GC cell viability, migration, and invasion, induced G0/G1 phase arrest and apoptosis, and suppressed tumor growth in vivo. Mechanistically, lnc-DNAJC3-AS1 was mainly localized in the cytoplasm and was associated with miR-576-5p-related RNA-induced silencing complex (RISC) complexes. MiR-576-5p targeted LYPLA1, and restoration of miR-576-5p or knockdown of LYPLA1 partially attenuated the effects of lnc-DNAJC3-AS1 overexpression on GC cell phenotypes and LYPLA1 enzymatic activity. These findings suggest that lnc-DNAJC3-AS1 promotes GC progression, at least in part, through the miR-576-5p/LYPLA1 pathway, providing a potential target for GC treatment.

Gastric cancer↗

PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗

PubMed2026

Cancer-associated fusion transcripts: mechanisms, functional roles, and clinical implications.

Fusion transcripts are hybrid RNA molecules generated through genomic rearrangements or RNA-level fusion mechanisms. They represent important molecular features of many cancers and can function as oncogenic drivers, diagnostic biomarkers, prognostic indicators, and therapeutic targets. Since the discovery of the BCR::ABL1 fusion in chronic myeloid leukemia, numerous cancer-associated fusion transcripts have been identified across hematologic malignancies and solid tumors. These fusion events encompass diverse biological mechanisms, including constitutively active kinases, aberrant transcription factors, epigenetic regulators, and non-coding fusion RNAs. This review summarizes current knowledge of the mechanisms underlying fusion transcript formation, including genomic rearrangement-dependent and rearrangement-independent processes, as well as fusion circular RNAs. The functional roles of fusion transcripts in cancer biology and their clinical relevance as diagnostic, prognostic, and predictive biomarkers are discussed. In addition, recent advances in fusion transcript detection and characterization are reviewed, including next-generation sequencing, long-read sequencing, single-cell approaches, artificial intelligence-assisted computational methods, and CRISPR/Cas9-mediated strategies for functional modeling and functional validation of fusion transcripts. Despite the rapid expansion of fusion transcript catalogs, the biological and clinical significance of most identified fusion events remains incompletely understood. Future progress will depend on integrating advanced sequencing technologies, artificial intelligence-assisted computational prioritization, and systematic functional validation to distinguish clinically actionable fusion transcripts from biologically neutral events. Such multidisciplinary approaches will be essential for translating fusion transcript research into precision oncology and improving cancer diagnosis, patient stratification, and targeted therapy.

Humans↗

PubMed2026

Non-coding RNAs as regulators of chromosomal instability in breast cancer.

Breast cancer is a highly heterogeneous disease characterized by extensive genomic and chromosomal instability (CIN), a hallmark that drives tumor evolution, intratumoral heterogeneity, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that non-coding RNAs (ncRNAs) are important regulators of genome maintenance and chromosome stability. However, their specific contributions to CIN and the strength of the available evidence remain incompletely understood. This review examines the role of the major ncRNA classes, including circular RNAs, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, and long non-coding RNAs, in the regulation of CIN-related processes in breast cancer. We discuss the molecular mechanisms by which these ncRNAs regulate key pathways involved in CIN, while critically evaluating the strength of the experimental evidence supporting their functional roles. We also examine their associations with distinct breast cancer molecular subtypes and assess their potential as biomarkers and therapeutic targets, highlighting current limitations and knowledge gaps that hinder clinical translation. Collectively, the available evidence supports an emerging role for ncRNAs as regulators of CIN while underscoring the need for further mechanistic and subtype-specific studies to validate their clinical utility.

DNA repair↗

PubMed2025

Expression analysis of LINC00671 and LINC01913 long non-coding RNAs in gastric cancer patients and their correlation with EMT markers.

BACKGROUND: Long-chain non-coding RNAs (lncRNAs) play various roles in the regulation of gene expression at the levels of transcription and translation, and epigenetic modification. Dysregulation of lncRNAs is associated with various malignancies, including cancer. lncRNAs have been demonstrated to regulate critical biological processes in cancer cells, such as apoptosis, proliferation, migration, and invasion. They also play essential roles in the development of gastric cancer (GC). However, the clinical significance and biological function of many lncRNAs remain unexplored in GC progression. This study aimed to evaluate the expression profiles of LINC00671 and LINC01913 in GC patients and investigate their correlation with epithelial-to-mesenchymal transition (EMT) markers. METHOD: The real-time PCR technique was applied to measure the expression levels of the selected lncRNAs (LINC01913 and LINC00671) and EMT-related mRNAs (MAMLs and MMP-13) in 83 tumor and adjacent normal tissues obtained from GC patients. RESULT: A significant reduction in LINC00671 expression was observed in 55.4% of tumor tissues, while elevated expression of LINC01913 (41%), MMP13 (56.6%), and MAML1 (44.6%) was detected, representing the proportion of samples with dysregulated expression relative to matched normal tissues. Dysregulation of these genes was significantly associated with various clinicopathological features (P < 0.05), supporting a potential link between these lncRNAs and EMT processes in GC. CONCLUSION: The observed associations between LINC00671, LINC01913, and EMT-related genes suggest their potential as prognostic biomarkers for treatment response in GC patients.

Humans↗

PubMed2026

LINC01871-Mediated Sensitivity to Cyclin-Dependent Kinase 4/6 Inhibitors in Human Breast Cancer.

Breast cancer remains the most frequently diagnosed malignancy in women, and resistance to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors limits long-term treatment efficacy. This study aimed to identify long non-coding RNAs (lncRNAs) associated with predicted sensitivity to CDK4/6 inhibitors and to investigate their biological functions in breast cancer. Transcriptomic data from The Cancer Genome Atlas (TCGA) and drug sensitivity data from the Genomics of Drug Sensitivity in Cancer 2 (GDSC2) database were integrated, and drug sensitivity was predicted using the oncoPredict algorithm. Candidate lncRNAs were identified through differential expression analysis, weighted gene co-expression network analysis, prognostic analysis, and machine learning. The biological functions of LINC01871 were subsequently evaluated using in vitro and in vivo experiments. Sixty-two lncRNAs associated with predicted sensitivity to ribociclib and palbociclib were identified, and six core lncRNAs were selected. LINC01871 showed the highest discriminatory performance for predicted drug sensitivity. Overexpression of LINC01871 was associated with increased sensitivity of breast cancer cells to ribociclib and palbociclib, inhibition of cell proliferation, promotion of apoptosis, and suppression of nuclear factor kappa B (NF-κB) signaling. Single-cell transcriptomic analysis demonstrated high LINC01871 expression in T cells and natural killer (NK) cells, while transcriptome-based immune infiltration analyses showed that high LINC01871 expression was associated with increased immune infiltration. These findings identify LINC01871 as a candidate biomarker of sensitivity to CDK4/6 inhibitors and demonstrate its tumor-suppressive effects in breast cancer. Further clinical and mechanistic studies are required to validate its predictive value and therapeutic relevance.

Humans↗

PubMed2024

Exploring the transcriptional cooperation between RUNX2 and its associated elncRNA RAIN.

Recent insights into the mechanisms controlling gene expression identified enhancer-associated long non-coding RNAs (elncRNAs) as master players of transcription in cancers. RUNX2, a mammalian RUNT-related transcription factor, is increasingly recognized in cancer biology for its role in supporting survival and progression also in thyroid cancer (TC). We recently identified, within the RUNX2 locus, a novel elncRNA that we named RAIN (RUNX2 associated intergenic lncRNA). We showed that RAIN and RUNX2 expression correlate in TC, both in vitro and in vivo, and that RAIN promotes RUNX2 expression by interacting with and affecting the activity of the RUNX2 P2 promoter through two distinct mechanisms. Here, we took forward these observations to explore the genome-wide transcriptional function of RAIN and its contribution to the RUNX2-dependent gene expression program in TC. By combining multiple omics data, we demonstrated that RAIN functionally cooperates with RUNX2 to the regulation of a subset of functionally related genes involved in promoting matrix remodeling, migration, and loss of differentiation. We showed that RAIN interacts with RUNX2 and its expression is required for the efficient recruitment of this TF to its target regulatory regions. In addition, our data revealed that besides RUNX2, RAIN governs a hierarchically organized complex transcriptional program by controlling a core of cancer-associated TFs that, in turn, orchestrate the expression of downstream genes. This evidence indicates that the functional cooperation observed between RAIN and RUNX2 can be a diffuse work mechanism for this elncRNA.

Core Binding Factor Alpha 1 Subunit↗

PubMed2017

Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.

The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering. The research community is building on these advances to develop more tailored delivery approaches and to tweak the genome in new and unique ways. Intertwining these approaches with newly engineered rAAV vectors is greatly expanding the available tools to manipulate gene expression with a therapeutic intent.

Dependovirus↗

PubMed2026

Comparative transcriptome analysis of Qinchuan and Wagyu cattle reveals lnc11599 as a negative regulator of intramuscular fat deposition.

BACKGROUND: Intramuscular fat (IMF) content is a critical factor determining beef quality, influenced by various factors including breed and age. However, the regulatory role of long non-coding RNAs (lncRNAs) in IMF deposition remains unclear. METHODS: This study investigated IMF deposition in the longissimus dorsi muscle of one- and two-year-old Qinchuan and Wagyu cattle through histological examination and fat content measurement. Based on transcriptome sequencing data of intramuscular fat tissue, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify lncRNAs associated with IMF deposition. The effects of a key candidate lncRNA on the adipogenic differentiation of cattle intramuscular preadipocytes were further examined. RESULTS: Results showed that Wagyu cattle exhibited stronger IMF deposition capacity than Qinchuan cattle across all age groups, with IMF content increasing with age in both breeds. We identified 7,910 lncRNAs from intramuscular fat tissue transcriptome data, including 6,455 novel lncRNAs. Through integrated differential expression analysis and WGCNA, 88 lncRNAs closely associated with IMF deposition were screened from two-year-old Qinchuan and Wagyu cattle. Notably, lnc11599 was significantly upregulated in Qinchuan cattle intramuscular fat tissue, but its expression decreased during intramuscular preadipocyte differentiation. Functional experiments demonstrated that lnc11599 knockdown enhanced adipogenic differentiation capacity, manifested as a highly significant increase in lipid accumulation, upregulation of key adipogenic genes at the mRNA level, together with increases in total fatty acid content and unsaturated fatty acid proportion. CONCLUSIONS: This study established the lncRNA expression profiles in intramuscular fat tissue of Qinchuan and Wagyu cattle across different developmental stages, and demonstrated that lnc11599 acts as a negative regulator of intramuscular fat deposition. These findings provide new directions for elucidating the mechanisms of cattle IMF deposition and offer potential targets for genetic improvement of beef quality.

Animals↗

PubMed2026

The regulatory role of non-coding RNAs in taxane resistance of breast cancer.

Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context‑dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane‑sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.

Breast cancer↗

PubMed2026

Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression.

The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This "local activation-global suppression" paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance.

Humans↗

PubMed2026

RNA splicing and cardiovascular disease: a guide for cardiologists.

Alternative splicing (AS) is a fundamental RNA processing mechanism, which generates different RNA transcripts and consequently different protein isoforms from a single gene. This increases the diversity of proteins within an organism and can fine-tune biological processes. This review examines how cardiac-enriched RNA-binding proteins establish heart-specific splicing programs governing aspects of cardiac development, function, and disease. Developmentally, coordinated sarcomeric isoform switches underpin the foetal-to-adult transition and further isoform rewiring in ion channel and kinase genes determine electrophysiology and excitation-contraction coupling. AS contributes to the pathogenesis of several cardiomyopathies and emerging datasets suggest that pathological hypertrophy engages distinct splicing signatures compared with physiological hypertrophy. This review summarizes diagnostic and prognostic opportunities arising from bulk, long-read, and single-cell/nucleus transcriptomics, which resolve cell type-specific isoforms and disease-associated switches. Circulating RNA biomarkers (including splice ratios and circularRNAs) may signify myocardial remodelling and arrhythmic risk. Integrative approaches that link AS with proteomics and genomics improve variant interpretation, reveal previously unannotated protein isoforms, and enable tracking of disease progression and therapy response. Finally, an outline of therapeutic strategies to modulate AS in cardiovascular disease (CVD), including antisense oligonucleotides, small molecules, and genome-editing modalities (CRISPR, base, and prime editing), is provided. The major challenges that remain before splice-targeting therapeutics can be targeted to treat cardiovascular disease are highlighted. Lessons from neuromuscular indications establish clinical feasibility of splicing correction and motivate translation to cardiology. Together, mechanistic insight, biomarker development, and therapeutic innovation position RNA splicing as a tractable axis for precision cardiovascular medicine.

Humans↗

PubMed2026

A Comparative Analysis of the Methylation Status of Non-Coding RNA Promoters in Fibroid and Matched Myometrium.

Uterine fibroids exhibit dysregulated expression of non-coding RNAs (ncRNAs), although the underlying mechanisms remain incompletely understood. We investigated promoter DNA methylation and its relationship with ncRNA expression in fibroids. Genomic DNA from eight paired fibroid and matched myometrial tissues was analyzed using MeDIP-chip to identify differentially methylated ncRNA promoters. Selected candidates were validated by methylation-specific PCR (MSP) in 16 paired samples, and transcript expression was assessed by qRT-PCR in 68-94 paired specimens. MeDIP-chip identified 538 lncRNAs and 61 miRNAs with differential promoter methylation, including 300 hypermethylated and 238 hypomethylated lncRNAs and 47 hypermethylated and 14 hypomethylated miRNAs. Promoter methylation was not significantly correlated with transcript expression (r = -0.1224). MSP confirmed hypermethylation of LINC-PINT and MIR9-3 and hypomethylation of WT1-AS and TTLL10-AS1. Correspondingly, LINC-PINT and MIR9-3 expression was decreased, whereas WT1-AS and TTLL10-AS1 expression was increased in fibroids. However, LINC-PINT and TTLL10-AS1 methylation did not fully correspond with MeDIP-chip findings. These results reveal widespread ncRNA promoter methylation alterations in uterine fibroids but demonstrate that genome-wide methylation does not consistently predict transcript expression, highlighting the complexity of ncRNA epigenetic regulation and the importance of locus-specific validation.

Humans↗

PubMed2026

Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.

Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.

Humans↗

PubMed2026

Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donor's and recipient's genetic factors associated with CLAD. METHOD: We genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable logistic regression models corrected for age, sex, initial disease and genetic ancestry. Three levels of explanatory variables were separately considered to conduct GWAS: donors-only, recipients-only, and donor-recipient mismatches. We also ran HLA-centric analyses using the same models. RESULTS: Our analysis confirmed the deleterious impact of HLA allelic and epitopic mismatches on CLAD risk, mostly driven by class I HLA (p=0.004). No significant associations with CLAD were found for donors' genotypes or donor-recipient non-HLA mismatches. We highlighted two independent recipient's loci associated with CLAD, including one protective signal (0.39 in CLAD vs 0.66 in non-CLAD recipients, p-value=5.05×10-7, q-value=0.017, OR=0.35) encompassing the PLXDC2 gene, and one risk signal (0.66 in CLAD vs 0.38 in non-CLAD recipients, p-value=9.86×10-7, q-value=0.017, OR=2.83) encompassing the ZNF518A/BLNK genes. These non-coding SNPs are putative regulatory variants of gene expression. Importantly, our single-cell RNA-sequencing showed a down-regulation of PLXDC2 in fibroblasts and lung epithelium in CLAD vs healthy controls. CONCLUSION: This first LT GWAS revealed two candidate loci from the recipient's genome, both biologically relevant for CLAD pathogenesis. Our study calls for larger LT genomic initiatives to increase power for signal discovery.

Humans↗