Non-coding RNA Research最新文献_第2页

Noncoding RNAs are indispensable architects and regulators of biomolecular condensates 非编码rna是生物分子凝聚不可缺少的构建者和调控者

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2026-01-16 DOI: 10.1016/j.ncrna.2026.01.003

Shiyuan Chen , Canchen Wang , Junyi Hu, Ting Luo, Qian Li, Hui Shen

Liquid-liquid phase separation (LLPS) is a biophysical mechanism by which certain biomolecules demix from the cytosol or nucleoplasm to form membraneless organelles. These droplet-like assemblies are dynamic and reversible, allowing selective enrichment of specific proteins and nucleic acids while excluding others. Classical examples include the nucleolus, P-bodies, and stress granules, all of which exhibit liquid-like behaviors such as rapid fusion, fission, and molecular exchange. Most importantly, the LLPS property has been implicated with a plethora of physiological and pathological processes. Historically, research on LLPS focused on protein drivers, especially RNA-binding proteins (RBPs) with low complexity domains or intrinsically disordered regions, contributing to multivalent weak interactions. However, it is now clear that RNA molecules especially noncoding RNAs are integral components and often active modulators of these condensates. Noncoding RNAs, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and others, can serve as scaffolds, regulators, or clients within the LLPS droplets, thereby influencing both normal cellular organization and disease processes. This review provides an overview of current research on how ncRNAs contribute to LLPS across different cellular localizations and contexts, covering physiological condensates, disease linked phase separation, underlying molecular mechanisms, and emerging therapeutic implications.

液-液相分离（LLPS）是一种生物物理机制，通过这种机制，某些生物分子从细胞质或核质中分离出来，形成无膜细胞器。这些液滴样的组装是动态的和可逆的，允许选择性地富集特定的蛋白质和核酸，同时排除其他的。典型的例子包括核仁、p体和应力颗粒，它们都表现出类似液体的行为，如快速聚变、裂变和分子交换。最重要的是，LLPS特性与大量的生理和病理过程有关。历史上，对LLPS的研究主要集中在蛋白质驱动因素上，特别是具有低复杂性结构域或内在无序区域的rna结合蛋白（rbp），有助于多价弱相互作用。然而，现在很清楚的是，RNA分子，特别是非编码RNA是这些凝聚物的组成部分，通常是活性调节剂。非编码rna，包括长链非编码rna （lncRNAs）、微rna （miRNAs）、环状rna （circRNAs）、piwi相互作用rna （piRNAs）等，可以作为LLPS液滴内的支架、调节剂或客户端，从而影响正常的细胞组织和疾病过程。这篇综述综述了目前关于ncRNAs如何在不同的细胞定位和背景下促进LLPS的研究，包括生理凝聚、疾病相关相分离、潜在的分子机制和新出现的治疗意义。

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引用次数: 0

Exosomal miRNA-218–5p derived from low-passage dermal papilla cells modulates hair follicle growth and development 来自低传代真皮乳头细胞的外泌体miRNA-218-5p调节毛囊的生长发育

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2026-01-15 DOI: 10.1016/j.ncrna.2026.01.004

Bohao Zhao , Jiawei Cai , Miaocheng Wang , Jiali Li , Shuyu Yao , Zhiyuan Bao , Yang Chen , Xinsheng Wu

Exosomes are nanoscale particles that participate in multiple biological processes and are secreted by various cell types. Exosomes derived from dermal papilla cells (DPC-Exos) regulate hair follicle (HF) growth and development. In this study, HF development-related genes were significantly expressed in low-passage dermal papilla cells (DPCs). Low-passage DPC-Exos promoted hair follicle stem cell (HFSC) proliferation. After the collection of DPC-Exos, miRNA sequencing identified 36 differentially expressed (DE) miRNAs between low-passage and high-passage DPC-Exos. Among these, miR-218–5p was significantly upregulated in low-passage DPC-Exos and dysregulated HF growth and development-related gene expression in HFSCs. Furthermore, the transport mechanism of exosomal miR-218–5p from DPCs is into HFSCs was verified. RNA sequencing of HFSCs treated with exosomal miR-218–5p identified differentially expressed genes (DEGs). The results indicated involvement of miR-218–5p in signaling pathways related to HF growth and development. Additionally, in vitro HF organ culture experiments demonstrated that exosomal miR-218–5p actively promotes hair growth. In summary, low-passage DPC-Exos enhance HFSC proliferation. Exosomal miR-218–5p may serve as a biomarker and therapeutic target for human hair disorders and as a tool to improve wool production in mammals.

外泌体是参与多种生物过程的纳米级颗粒，由各种细胞类型分泌。来自真皮乳头细胞的外泌体（DPC-Exos）调节毛囊（HF）的生长发育。在本研究中，HF发育相关基因在低传代真皮乳头细胞（DPCs）中显著表达。低传代DPC-Exos促进毛囊干细胞（HFSC）增殖。收集DPC-Exos后，miRNA测序在低传代和高传代DPC-Exos之间鉴定出36个差异表达（DE） miRNA。其中，miR-218-5p在低传代DPC-Exos中显著上调，在HFSCs中HF生长发育相关基因表达失调。此外，证实了外泌体miR-218-5p从DPCs转运到HFSCs的机制。外泌体miR-218-5p处理的HFSCs的RNA测序鉴定出差异表达基因（DEGs）。结果表明miR-218-5p参与与HF生长和发展相关的信号通路。此外，体外HF器官培养实验表明，外泌体miR-218-5p积极促进头发生长。综上所述，低传代DPC-Exos增强了HFSC的增殖。外泌体miR-218-5p可能作为人类毛发疾病的生物标志物和治疗靶点，并作为提高哺乳动物羊毛产量的工具。

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引用次数: 0

Mechanistic roles of long non-coding RNAs in gastric cancer therapy resistance 长链非编码rna在胃癌耐药中的机制作用

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2026-01-06 DOI: 10.1016/j.ncrna.2025.12.004

Jiayi Chen , Juanmei Gao

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. While gastrointestinal tumor screening has reduced incidence and mortality, its treatment faces is hindered by challenges including chemotherapy resistance and poor prognosis. Long non-coding RNAs (lncRNAs), a class of non-coding RNAs exceeding 200 nucleotides in length, serve as pivotal regulators in GC pathogenesis and therapeutic resistance. This review comprehensively summarizes the mechanistic roles of lncRNAs in chemotherapy, immunotherapy, and targeted therapy resistance for GC. In chemotherapy, lncRNAs modulate drug sensitivity to fluoropyrimidines (5-FU), platinum-based agents and other chemotherapeutics by regulating autophagy, apoptosis, metabolic reprogramming and DNA damage repair mechanisms, such as HNF1A-AS1, LINC00942 and CRNDE. In immunotherapy, lncRNAs influence immune checkpoint inhibitor efficacy by regulating PD-L1 expression, tumor microenvironment (TME), and macrophage polarization (e.g., LINC01094, MIR4435-2HG). Notably, specific lncRNAs (e.g., LINC00665, HOTAIR) contribute to resistance against HER2-targeted and anti-angiogenic therapies. Although current research remains exploratory, lncRNAs show significant promise as predictive biomarkers and therapeutic targets. Future personalized strategies intergrating lncRNA profiles could help overcome drug resistance and improve patient outcomes.

胃癌（GC）仍然是世界范围内癌症相关死亡的主要原因。虽然胃肠道肿瘤筛查降低了发病率和死亡率，但其治疗面临化疗耐药和预后差等挑战。长链非编码rna （Long non-coding rna, lncRNAs）是一类长度超过200个核苷酸的非编码rna，在胃癌发病机制和治疗耐药中起关键调节作用。本文综述了lncrna在胃癌化疗、免疫治疗和靶向治疗耐药中的作用机制。在化疗中，lncRNAs通过调节自噬、凋亡、代谢重编程和DNA损伤修复机制，如HNF1A-AS1、LINC00942和CRNDE等，调节对氟嘧啶（5-FU）、铂类药物等化疗药物的药物敏感性。在免疫治疗中，lncrna通过调节PD-L1表达、肿瘤微环境（TME）和巨噬细胞极化（如LINC01094、MIR4435-2HG）来影响免疫检查点抑制剂的疗效。值得注意的是，特异性lncRNAs（例如，LINC00665， HOTAIR）有助于抵抗her2靶向和抗血管生成治疗。尽管目前的研究仍处于探索性阶段，但lncrna作为预测性生物标志物和治疗靶点显示出巨大的前景。未来整合lncRNA谱的个性化策略可能有助于克服耐药性并改善患者预后。

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引用次数: 0

SNHG5 enhances colorectal cancer metastasis through RNA–protein interaction with GNB2 and activation of canonical Wnt signaling SNHG5通过rna -蛋白与GNB2的相互作用和典型Wnt信号的激活促进结直肠癌转移

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2026-01-02 DOI: 10.1016/j.ncrna.2025.12.002

Xinyi Chen , Mu Yang , Xiaoxiao Luo, Xianglin Yuan

Background and purpose

Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies worldwide, with distant metastasis—particularly to the liver—representing the primary cause of poor prognosis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of CRC progression, yet the mechanisms by which they modulate G protein signaling during hepatic metastasis remain unclear. This study aimed to determine the role of the lncRNA SNHG5 in CRC liver metastasis and to explore whether G protein–related mechanisms are involved in this process.

Methods

We established murine MC38 CRC sublines with distinct metastatic capacities (F0 and F3) and performed RNA sequencing to identify key lncRNAs. Biotin-labeled RNA pull-down coupled with mass spectrometry was used to identify SNHG5-interacting proteins. The SNHG5–GNB2 interaction was validated using RIP, RNA-FISH, and Western blot analyses. Functional rescue assays, in vivo liver metastasis models, and Wnt pathway activity measurements were conducted to delineate downstream effects. Public transcriptomic datasets from GEO and TCGA were used to assess the expression patterns and prognostic relevance of SNHG5 and GNB2 in CRC and metastatic lesions.

Results

SNHG5 was significantly upregulated in the highly metastatic F3 subline and predominantly localized in the cytoplasm. Pull-down and proteomic analysis identified GNB2, a classical G protein β-subunit, as a direct binding partner of SNHG5. Functionally, SNHG5 promoted cell proliferation, migration, epithelial–mesenchymal transition (EMT), and suppressed apoptosis, while GNB2 overexpression partially rescued the tumor-suppressive phenotypes induced by SNHG5 silencing. Mechanistically, the SNHG5–GNB2 axis enhanced Wnt/β-catenin signaling via increased p-GSK3β and β-catenin levels, thereby driving EMT. Transcriptomic analyses further revealed that GNB2 is upregulated in CRC and liver metastases and is associated with poor prognosis. Multi-omics data suggested additional roles for this axis in immune evasion, metabolic reprogramming, and remodeling of the metastatic microenvironment.

Conclusion

This study provides the first evidence that SNHG5 promotes CRC liver metastasis through direct interaction with GNB2 and subsequent activation of the Wnt/β-catenin pathway. The SNHG5–GNB2 axis orchestrates a multilayered regulatory network that integrates EMT induction, immune suppression, and metabolic adaptation, highlighting its potential as a mechanistic driver and therapeutic target in metastatic CRC.

背景和目的结直肠癌（CRC）是世界范围内最常见和最致命的恶性肿瘤之一，其远处转移（尤其是肝脏）是导致预后不良的主要原因。长链非编码rna （lncRNAs）已成为结直肠癌进展的关键调节因子，但它们在肝转移过程中调节G蛋白信号的机制尚不清楚。本研究旨在确定lncRNA SNHG5在结直肠癌肝转移中的作用，并探讨G蛋白相关机制是否参与这一过程。方法建立具有不同转移能力（F0和F3）的小鼠MC38 CRC亚群，并进行RNA测序以鉴定关键lncrna。生物素标记RNA下拉联用质谱法鉴定snhg5相互作用蛋白。SNHG5-GNB2相互作用通过RIP、RNA-FISH和Western blot分析验证。通过功能恢复实验、体内肝转移模型和Wnt通路活性测量来描述下游效应。来自GEO和TCGA的公共转录组数据用于评估SNHG5和GNB2在结直肠癌和转移性病变中的表达模式和预后相关性。结果snhg5在高转移性的F3亚系中表达显著上调，且主要定位于细胞质中。Pull-down和蛋白质组学分析发现，GNB2是一个经典的G蛋白β亚基，是SNHG5的直接结合伙伴。功能上，SNHG5促进细胞增殖、迁移、上皮-间质转化（epithelial-mesenchymal transition， EMT），抑制细胞凋亡，而GNB2过表达部分恢复了SNHG5沉默诱导的肿瘤抑制表型。机制上，SNHG5-GNB2轴通过增加p-GSK3β和β-catenin水平增强Wnt/β-catenin信号传导，从而驱动EMT。转录组学分析进一步显示，GNB2在结直肠癌和肝转移中表达上调，并与预后不良相关。多组学数据表明，该轴在免疫逃避、代谢重编程和转移性微环境重塑中具有其他作用。结论本研究首次证实SNHG5通过与GNB2直接相互作用并随后激活Wnt/β-catenin通路促进结直肠癌肝转移。SNHG5-GNB2轴协调了一个多层调控网络，整合了EMT诱导、免疫抑制和代谢适应，突出了其作为转移性结直肠癌的机制驱动和治疗靶点的潜力。

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引用次数: 0

Epigenetic H3K4me3 activation of miR-155-5p promotes intervertebral disc degeneration via autophagy and ageing in nucleus pulposus cells 表观遗传H3K4me3激活miR-155-5p通过髓核细胞的自噬和老化促进椎间盘退变

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-26 DOI: 10.1016/j.ncrna.2025.12.001

Ximeng Wang , Hanqiu Sun , Wenbiao Xiao , Yuxuan Zhang , Xiao Lu , Zhaoyang Gong , Dachuan Li , Siyang Liu , Xinlei Xia , Hongli Wang , Minghao Shao , Guangyu Xu , Xiaosheng Ma

Nucleus pulposus (NP) cell ageing and impaired autophagy - lysosome biogenesis (ALB) are key drivers of intervertebral disc degeneration (IVDD). The upstream epigenetic regulation of transcription factor EB (TFEB), a major ALB regulator, remains elusive. Our study identifies a H3K4me3-associated miRNA pathway that modulates TFEB activity and IVDD progression. Using in vivo and in vitro models, we found that methyltransferase MLL3 knockdown reduces H3K4me3 methylation at the miR-155-5p promoter, suppressing miR-155-5p transcription. MiR-155-5p directly targets FBXO22, indirectly repressing TFEB transcription and exacerbating NP cells ageing and IVDD. Notably, experiments confirmed MLL3 binds specifically to the miR-155-5p promoter, with no interaction detected at the TFEB or FBXO22 promoters. Our data establish a linear H3K4me3/miR-155-5p/FBXO22/TFEB axis in IVDD pathogenesis. We reveal a novel epigenetic crosstalk where H3K4me3 methylation mediates miRNA-driven TFEB regulation, independent of canonical mTOR signaling. These findings enhance understanding of epigenetic mechanisms in autophagy and ageing control and highlight MLL3 and miR-155-5p as potential IVDD therapeutic targets.

髓核（NP）细胞老化和自噬-溶酶体生物发生受损（ALB）是椎间盘退变（IVDD）的关键驱动因素。转录因子EB （TFEB）是ALB的主要调控因子，其上游表观遗传调控尚不明确。我们的研究确定了一个h3k4me3相关的miRNA通路，该通路调节TFEB活性和IVDD进展。通过体内和体外模型，我们发现甲基转移酶MLL3敲低降低了miR-155-5p启动子处的H3K4me3甲基化，抑制了miR-155-5p的转录。MiR-155-5p直接靶向FBXO22，间接抑制TFEB转录，加剧NP细胞老化和IVDD。值得注意的是，实验证实MLL3特异性结合miR-155-5p启动子，而在TFEB或FBXO22启动子上未检测到相互作用。我们的数据在IVDD发病机制中建立了H3K4me3/miR-155-5p/FBXO22/TFEB线性轴。我们揭示了一种新的表观遗传串扰，其中H3K4me3甲基化介导mirna驱动的TFEB调控，独立于典型的mTOR信号传导。这些发现增强了对自噬和衰老控制的表观遗传机制的理解，并强调了MLL3和miR-155-5p是潜在的IVDD治疗靶点。

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引用次数: 0

The crosstalk network of non-coding RNAs: Emerging opportunities for the clinical application of osteoporosis 非编码rna的串扰网络：骨质疏松症临床应用的新机遇

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-17 DOI: 10.1016/j.ncrna.2025.11.008

Chunlu Yan , Qiao Wan , Zeling Fang , Chuangwei Sui , Xiaolong Xiao , Fan Yang , Baoshan Di , Yajun Li , Juan Yu , Yana Zhao , Guoliang Liu , Yibo Zhou , Wei Li , Fangyu An

Current methods for testing bone density lack the capability to detect patients with early bone loss, and existing osteoporosis therapies have limitations in their efficacy and safety. Therefore, the development of more precise and convenient diagnostic technologies and novel treatments is of paramount importance. Extracellular vesicle (EV)-mediated non-coding RNA (ncRNA) interaction networks enable both the detection of early bone loss and targeted therapy for enhanced treatment outcomes. In this review, we highlight the utility of EVs for carrying various ncRNAs (e.g., miRNAs, lncRNAs, and circRNAs) and thereby forming a complex regulatory network amongst bone-related cells such as osteoblasts and osteoclasts. The mechanisms through which EVs regulate bone cells and their potential for clinical translation are described in detail. Although the EV-mediated ncRNA network holds great promise for the precise diagnosis and targeted treatment of osteoporosis, rigorous large-scale studies are still required to address challenges related to its specificity and clinical application.

目前检测骨密度的方法缺乏检测早期骨质流失患者的能力，并且现有的骨质疏松治疗方法在其有效性和安全性方面存在局限性。因此，开发更精确和方便的诊断技术和新的治疗方法至关重要。细胞外囊泡（EV）介导的非编码RNA （ncRNA）相互作用网络能够检测早期骨质流失和靶向治疗，从而提高治疗效果。在这篇综述中，我们强调了ev携带各种ncrna（例如，mirna， lncrna和circrna）的作用，从而在骨相关细胞（如成骨细胞和破骨细胞）之间形成复杂的调控网络。通过ev调节骨细胞的机制及其潜在的临床翻译进行了详细的描述。尽管ev介导的ncRNA网络在骨质疏松症的精确诊断和靶向治疗方面具有很大的前景，但仍需要严格的大规模研究来解决其特异性和临床应用方面的挑战。

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引用次数: 0

Hsa_circ_0101645 contributes to excessive autophagy and apoptosis in intervertebral disc degeneration by acting as a miR-1304-5p sponge modulating BNIP3 expression Hsa_circ_0101645通过作为miR-1304-5p海绵调节BNIP3表达，参与椎间盘退变中过度自噬和凋亡

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-16 DOI: 10.1016/j.ncrna.2025.11.007

Jianhai Luo , Tong Yu , Pengcheng Hu , Jie Liu

Background

Intervertebral disc (IVD) degeneration (IVDD) is the pathological foundation and principal cause for degenerative spine related diseases. Currently, its molecular pathogenesis and reliable biomarkers remain poorly understood. This study intends to elucidate the potential molecular mechanisms of circular RNAs (circRNAs) in IVDD, and to identify novel targeted therapeutic strategies.

Methods

Differentially expressed circRNAs (DE-circRNAs) were obtained by a secondary analysis of the IVDD-related dataset GSE67566, followed by enrichment analysis of their host genes. Both in vitro mechanical loading-induced and in vivo tail suspension-induced models were applied to validate the functions of hsa_circ_0101645, miRNA-1304-05p, and BCL2 Interacting Protein 3 (BNIP3) in IVDD. The competing endogenous RNA (ceRNA) mechanism involving hsa_circ_0101645/miR-1304-5p/BNIP3 was authenticated using dual luciferase reporter genes, Argonaute2-RNA binding protein immunoprecipitation, and RNA-RNA pull down.

Results

In the bioinformatics, there were 354 significantly down-regulated and 282 up-regulated DE-circRNAs in IVDD. The host genes of these circRNAs were mainly enriched in cell morphogenesis, autophagy, and apoptosis. In clinical samples, hsa_circ_0101645 in DE-circRNAs was markedly overexpressed in endplate chondrocytes (EPC) derived from IVDD patients and was predominantly localized in the cytoplasm. In vitro, overexpression of hsa_circ_0101645 and BNIP3, or knockdown of miR-1304-5p, dramatically diminished EPC viability and enlarged apoptosis and autophagic flux. In vivo, sa_circ_0101645 knockdown alleviated structural collapse and tissue lesions in the cartilage endplates, nucleus pulposus and annulus fibrosus of the IVD. Mechanistically, Hsa_circ_0101645 upregulated BNIP3 expression by serving as miR-1304-5p sponge.

Conclusions

Hsa_circ_0101645 service as ceRNA that facilitates IVDD process by mediating proliferation, apoptosis, and excessive autophagy of CEP via the miR-1304-5p/BNIP3 axis. These findings suggest that hsa_circ_0101645 represents a promising molecular target for IVDD therapy.

背景椎间盘退变是脊柱退行性疾病的病理基础和主要原因。目前，其分子发病机制和可靠的生物标志物仍知之甚少。本研究旨在阐明环状rna （circRNAs）在IVDD中的潜在分子机制，并确定新的靶向治疗策略。方法通过对ivdd相关数据集GSE67566进行二次分析获得差异表达的环状rna (DE-circRNAs)，然后对其宿主基因进行富集分析。采用体外机械负荷诱导和体内尾悬浮诱导模型验证hsa_circ_0101645、miRNA-1304-05p和BCL2相互作用蛋白3 （BCL2 Interacting Protein 3, BNIP3）在IVDD中的功能。通过双荧光素酶报告基因、Argonaute2-RNA结合蛋白免疫沉淀和RNA-RNA拉下验证了涉及hsa_circ_0101645/miR-1304-5p/BNIP3的竞争内源性RNA （ceRNA）机制。结果在生物信息学方面，在IVDD中有354个de - circrna显著下调，282个de - circrna显著上调。这些环状rna的宿主基因主要富集于细胞形态发生、自噬和凋亡。在临床样本中，DE-circRNAs中的hsa_circ_0101645在来自IVDD患者的终板软骨细胞（EPC）中显著过表达，并且主要定位于细胞质中。在体外，过表达hsa_circ_0101645和BNIP3，或敲低miR-1304-5p，显著降低EPC活力，增加凋亡和自噬通量。在体内，sa_circ_0101645敲低减轻了IVD软骨终板、髓核和纤维环的结构塌陷和组织病变。机制上，Hsa_circ_0101645通过充当miR-1304-5p海绵上调BNIP3的表达。结论shsa_circ_0101645通过miR-1304-5p/BNIP3轴介导CEP的增殖、凋亡和过度自噬，作为促进IVDD过程的ceRNA。这些发现表明hsa_circ_0101645代表了IVDD治疗的一个有希望的分子靶点。

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引用次数: 0

circ_0103896/miR-432–5p/FTO feedback loop suppresses the formation and progression of intracranial aneurysm circ_0103896/ miR-432-5p /FTO反馈回路抑制颅内动脉瘤的形成和发展

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-15 DOI: 10.1016/j.ncrna.2025.11.001

Zhiwen Lu , Shijie Zhu , Yina Wu , Fengfeng Xu , Qinghai Huang

Circular RNAs (circRNAs) and m⁶A RNA methylation play crucial roles in the pathogenesis of intracranial aneurysm (IA); however, their regulatory interplay remains unclear. Through circRNA profiling of 16 IA tissues and 8 superficial temporal arteries, we identified hsa_circ_0103896 as significantly downregulated in IA. RT-qPCR analysis further revealed that decreased circ_0103896 or increased miR-432–5p expression correlated with IA progression. Functional assays demonstrated that circ_0103896 inhibited the phenotypic switch of human brain vascular smooth muscle cells (hBVSMCs) from a contractile to a synthetic state, whereas circ_0103896 knockdown reversed this effect. In vivo, circ_0103896 overexpression alleviated IA severity, whereas its depletion aggravated aneurysm formation. Mechanistically, circ_0103896 functioned as a sponge for miR-432–5p, thereby upregulating FTO, which in turn promoted m⁶A demethylation of circ_0103896. This process reinforced circ_0103896 expression, forming a positive feedback loop. The circ_0103896/miR-432–5p/FTO axis thus suppresses hBVSMC phenotypic transformation and mitigates IA progression. These findings reveal a novel epigenetic mechanism involving m⁶A modification and circRNA–miRNA crosstalk in IA pathogenesis, highlighting circ_0103896 as a potential therapeutic target.

环状RNA （circRNAs）和m6A RNA甲基化在颅内动脉瘤（IA）的发病机制中发挥关键作用；然而，它们在监管方面的相互作用仍不清楚。通过16个IA组织和8个颞浅动脉的circRNA分析，我们发现hsa_circ_0103896在IA中显著下调。RT-qPCR分析进一步显示circ_0103896表达降低或miR-432-5p表达升高与IA进展相关。功能分析表明，circ_0103896抑制了人脑血管平滑肌细胞（hBVSMCs）从收缩状态到合成状态的表型转换，而circ_0103896敲低则逆转了这一作用。在体内，circ_0103896过表达减轻了IA的严重程度，而其缺失则加重了动脉瘤的形成。在机制上，circ_0103896作为miR-432-5p的海绵，从而上调FTO，进而促进circ_0103896的m6A去甲基化。这个过程强化了circ_0103896表达，形成了一个正反馈循环。circ_0103896/ miR-432-5p /FTO轴因此抑制hBVSMC表型转化并减轻IA进展。这些发现揭示了IA发病机制中涉及m6A修饰和circRNA-miRNA串扰的一种新的表观遗传机制，强调circ_0103896是潜在的治疗靶点。

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引用次数: 0

LncRNA ZFAS1 in hepatocellular carcinoma: A systematic review of molecular mechanisms and clinical translation LncRNA ZFAS1在肝细胞癌中的分子机制和临床翻译的系统综述

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-05 DOI: 10.1016/j.ncrna.2025.11.003

Peng Zhu , Hui-ying Liu

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with its high recurrence rate and therapeutic resistance underscoring the urgent need for breakthrough molecular targets. The long non-coding RNA ZFAS1 has emerged as a critical regulatory hub in HCC pathogenesis through its multidimensional mechanisms. Clinical investigations reveal significant ZFAS1 overexpression in HCC tissues, which is strongly associated with microvascular invasion, lymph node metastasis, and unfavorable clinical outcomes. Meta-analytical data further corroborate its independent prognostic value in survival prediction.

Mechanistically, ZFAS1 functions as a competitive endogenous RNA (ceRNA) that sequesters tumor-suppressive miRNAs including miR-150 and miR-193a-3p, thereby de-repressing downstream oncogenic targets such as ZEB1/MMP14 and RALY/HGF/c-Met. This molecular interplay drives epithelial-mesenchymal transition (EMT) and metastatic progression, while ZFAS1-encoded micropeptides concurrently inhibit ferroptosis through mitochondrial ROS modulation and the miR-150/AIFM2 axis, thereby synergistically enhancing tumor proliferation and apoptotic resistance. Within the tumor microenvironment (TME), exosome-derived ZFAS1 remodels intercellular communication networks, promoting angiogenesis via STAT3/VEGFA signaling, though its immunometabolic regulatory mechanisms warrant further elucidation. Clinically, plasma ZFAS1 demonstrates enhanced diagnostic utility when combined with alpha-fetoprotein (AUC = 0.891), while therapeutic targeting of ZFAS1-mediated PI3K-AKT and PERK/ATF4 pathways shows promise in overcoming sorafenib/donafenib resistance. Current translational challenges include ZFAS1 isoform heterogeneity, suboptimal liquid biopsy sensitivity, and dynamic TME interactions.

Future directions should employ multi-omics integration (spatial transcriptomics/single-cell sequencing) coupled with AI-driven network modeling to systematically decode ZFAS1's regulatory architecture, ultimately enabling precision theranostic strategies for HCC management.

肝细胞癌（HCC）仍然是全球癌症相关死亡的主要原因，其高复发率和治疗耐药性强调了迫切需要突破性的分子靶点。长链非编码RNA ZFAS1通过其多维机制成为HCC发病机制的关键调控枢纽。临床研究显示ZFAS1在HCC组织中显著过表达，与微血管侵袭、淋巴结转移及不良临床预后密切相关。meta分析数据进一步证实了其在生存预测中的独立预后价值。在机制上，ZFAS1作为竞争性内源性RNA (ceRNA)，隔离肿瘤抑制mirna，包括miR-150和miR-193a-3p，从而去抑制下游致癌靶标，如ZEB1/MMP14和RALY/HGF/c-Met。这种分子间相互作用驱动上皮-间质转化（EMT）和转移进展，而zfas1编码的微肽通过线粒体ROS调节和miR-150/AIFM2轴同时抑制铁凋亡，从而协同增强肿瘤增殖和凋亡抵抗。在肿瘤微环境（TME）中，外泌体衍生的ZFAS1重塑细胞间通讯网络，通过STAT3/VEGFA信号通路促进血管生成，尽管其免疫代谢调节机制有待进一步阐明。临床上，血浆ZFAS1联合甲胎蛋白（AUC = 0.891）显示出增强的诊断效用，而治疗靶向ZFAS1介导的PI3K-AKT和PERK/ATF4通路显示出克服索拉非尼/多纳非尼耐药的希望。目前的翻译挑战包括ZFAS1异构体异质性、次优液体活检敏感性和动态TME相互作用。未来的方向应该采用多组学整合（空间转录组学/单细胞测序），结合人工智能驱动的网络建模，系统地解码ZFAS1的调控结构，最终实现HCC管理的精确治疗策略。

{"title":"LncRNA ZFAS1 in hepatocellular carcinoma: A systematic review of molecular mechanisms and clinical translation","authors":"Peng Zhu , Hui-ying Liu","doi":"10.1016/j.ncrna.2025.11.003","DOIUrl":"10.1016/j.ncrna.2025.11.003","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with its high recurrence rate and therapeutic resistance underscoring the urgent need for breakthrough molecular targets. The long non-coding RNA ZFAS1 has emerged as a critical regulatory hub in HCC pathogenesis through its multidimensional mechanisms. Clinical investigations reveal significant ZFAS1 overexpression in HCC tissues, which is strongly associated with microvascular invasion, lymph node metastasis, and unfavorable clinical outcomes. Meta-analytical data further corroborate its independent prognostic value in survival prediction.</div><div>Mechanistically, ZFAS1 functions as a competitive endogenous RNA (ceRNA) that sequesters tumor-suppressive miRNAs including miR-150 and miR-193a-3p, thereby de-repressing downstream oncogenic targets such as ZEB1/MMP14 and RALY/HGF/c-Met. This molecular interplay drives epithelial-mesenchymal transition (EMT) and metastatic progression, while ZFAS1-encoded micropeptides concurrently inhibit ferroptosis through mitochondrial ROS modulation and the miR-150/AIFM2 axis, thereby synergistically enhancing tumor proliferation and apoptotic resistance. Within the tumor microenvironment (TME), exosome-derived ZFAS1 remodels intercellular communication networks, promoting angiogenesis via STAT3/VEGFA signaling, though its immunometabolic regulatory mechanisms warrant further elucidation. Clinically, plasma ZFAS1 demonstrates enhanced diagnostic utility when combined with alpha-fetoprotein (AUC = 0.891), while therapeutic targeting of ZFAS1-mediated PI3K-AKT and PERK/ATF4 pathways shows promise in overcoming sorafenib/donafenib resistance. Current translational challenges include ZFAS1 isoform heterogeneity, suboptimal liquid biopsy sensitivity, and dynamic TME interactions.</div><div>Future directions should employ multi-omics integration (spatial transcriptomics/single-cell sequencing) coupled with AI-driven network modeling to systematically decode ZFAS1's regulatory architecture, ultimately enabling precision theranostic strategies for HCC management.</div></div>","PeriodicalId":37653,"journal":{"name":"Non-coding RNA Research","volume":"17 ","pages":"Pages 44-53"},"PeriodicalIF":4.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145692651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TPR is required for circRNA, lncRNA and mRNA nuclear export TPR是circRNA、lncRNA和mRNA核输出所必需的

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-05 DOI: 10.1016/j.ncrna.2025.11.010

Min Zhou , Ruirui Jia , Mengya Gao , Jun Yang , Hongbo Qi

Background

Efficient RNA nuclear export is essential for proper cellular function and normal physiology, with defects in this process leading to pathological consequences. Our study aimed to investigate the role of translocated promoter region (TPR), nuclear basket protein, in orchestrating RNA transport in human cells as well as the function of TPR-mediated RNA nuclear export in cervical cancer cells.

Methods

RNA sequencing and bioinformatic analysis were applied to explore the effect of TPR on circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and mRNAs nuclear export and their corresponding sequence characteristic. Fluorescence in situ hybridization was employed to explore the role of TPR in RNA nuclear export. Immunofluorescence staining was used to study the role of TPR in R-loop and DNA damage. Flow cytometry assay was applied to investigate the influence of TPR on cell cycle in cervical cancer cells.

Results

TPR depletion leads to the nuclear accumulation of 7243 circRNAs, 1913 lncRNAs, and 2758 mRNAs. Codepletion and rescue experiments suggested that the modulation of TPR-mediated circRNAs nuclear export might be independent of XPO4. The regulation of TPR-mediated circRNAs nuclear export is independent of circRNAs characteristics, while, the regulation of TPR-mediated lncRNAs and mRNAs nuclear export is partly dependent on lncRNAs/mRNAs transcription length. Moreover, the lack of TPR results in nuclear R-loop accumulation, causing DNA damage and cell cycle arrest as well as subsequent inhibition of cell proliferation in cervical cancer cells.

Conclusions

This study highlights the nuclear export of circRNA, lncRNA and mRNA relies critically on TPR, a mechanism that may inhibit nuclear accumulation of R-loop and DNA damage in cervical cancer cells.

RNA核输出不足对正常的细胞功能和生理机能至关重要，这一过程中的缺陷会导致病理后果。本研究旨在探讨核筐蛋白易位启动子区（TPR）在人细胞RNA转运中的作用，以及TPR介导的RNA核输出在宫颈癌细胞中的功能。方法采用srna测序和生物信息学分析方法，探讨TPR对环状rna （circRNAs）、长链非编码rna （lncRNAs）和mrna核输出的影响及其相应的序列特征。采用荧光原位杂交技术探讨TPR在RNA核输出中的作用。免疫荧光染色法研究TPR在R-loop和DNA损伤中的作用。采用流式细胞术研究TPR对宫颈癌细胞周期的影响。结果stpr缺失导致7243个circrna、1913个lncrna和2758个mrna的核积累。Codepletion和rescue实验表明，tpr介导的circRNAs核输出的调节可能独立于XPO4。tpr介导的circRNAs核输出调控与circRNAs的特性无关，而tpr介导的lncRNAs和mrna核输出调控部分依赖于lncRNAs/ mrna的转录长度。此外，缺乏TPR会导致核r环积累，导致宫颈癌细胞DNA损伤和细胞周期阻滞，进而抑制细胞增殖。结论本研究强调circRNA、lncRNA和mRNA的核输出严重依赖于TPR，这一机制可能抑制宫颈癌细胞中R-loop的核积累和DNA损伤。

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引用次数: 0