CELL
·
2021
·
IF 41.584
Liming Yan,Yunxiang Yang,Mingyu Li,Ying Zhang,Litao Zheng,Ji Ge,Yucen C. Huang,Zhenyu Liu,Tao Wang,Shan Gao,Ran Zhang,Yuanyun Y. Huang,Luke W. Guddat,Yan Gao,Zihe Rao,Zhiyong Lou
The capping of mRNA and the proofreading play essential roles in SARS-CoV-2 replication and transcription. Here, we present the cryo-EM structure of the SARS-CoV-2 replication-transcription complex (RTC) in a form identified as Cap(0)-RTC, which couples a co-transcriptional capping complex (CCC) composed of nsp12 NiRAN, nsp9, the bifunctional nsp14 possessing an N-terminal exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase), and nsp10 as a cofactor of nsp14. Nsp9 and nsp12 NiRAN recruit nsp10/nsp14 into the Cap(0)-RTC, forming the N7-CCC to yield cap(0) ( 7Me GpppA) at 5′ end of pre-mRNA. A dimeric form of Cap(0)-RTC observed by cryo-EM suggests an in trans backtracking mechanism for nsp14 ExoN to facilitate proofreading of the RNA in concert with polymerase nsp12. These results not only provide a structural basis for understanding co-transcriptional modification of SARS-CoV-2 mRNA but also shed light on how replication fidelity in SARS-CoV-2 is maintained.
研究领域:
病毒学
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结构生物学
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分子生物学
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高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2021
·Vol. 236
·期 8
·5921-5936
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IF 6.384
Sijia Liang,Jing Luo,Muna Alariqi,Zhongping Xu,Aoli Wang,Muhammad Naeem Zafar,Jun Ren,Fuqiu Wang,Xuefei Liu,Yanfeng Xin,Haonan Xu,Weifeng Guo,Yanqin Wang,Weihua Ma,Lizhen Chen,Keith Lindsey,Xianlong Zhang,Shuangxia Jin
Plant bugs (Miridae species) have become major agricultural pests that cause increasing and severe economic damage. Plant-mediated RNA interference (RNAi) is emerging as an eco-friendly, efficient, and reliable strategy for pest management. In this study, we isolated and characterized a lethal gene of Apolygus lucorum and named it Apolygus lucorum LIM ( AlLIM ), which produced A. lucorum mortality rates ranging from 38% to 81%. Downregulation of the AlLIM gene expression in A. lucorum by injection of a double-stranded RNA (dsRNA) led to muscle structural disorganization that resulted in metamorphosis deficiency and increased mortality. Then we constructed a plant expression vector that enabled transgenic cotton to highly and stably express dsRNA of AlLIM ( dsAlLIM ) by Agrobacterium -mediated genetic transformation. In the field bioassay, dsAlLIM transgenic cotton was protected from A. lucorum damage with high efficiency, with almost no detectable yield loss. Therefore, our study successfully provides a promising genetically modified strategy to overpower A. lucorum attack.
研究领域:
植物保护
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分子生物学
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农业科学
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高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
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IF 3.9
Wu Zhiwei,Zhang Fan,Yang Kai,He Wenfei
Breast cancer is the leading cause of cancer-related death in women worldwide, and its developmental mechanisms involve complex factors. Recent studies have shown that ferroptosis is closely related to the occurrence and progression of breast cancer. However, the role of circular RNAs (circRNAs) in regulating ferroptosis in breast cancer remains unclear. In this study, we investigated the regulatory role of circSCD1 (hsa_circ_0019512) in breast cancer. We examined the expression of circSCD1 in breast cancer cell lines and explored its impact on cell viability and colony formation. We also evaluated the involvement of circSCD1 in ferroptosis by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular iron. In vivo xenograft experiments were performed to confirm the role of circSCD1 in promoting tumor growth and inhibiting ferroptosis.Furthermore, we investigated the mechanism by which circSCD1 regulates SCD1 protein stability through ubiquitination and identified the interaction between circSCD1 and the deubiquitinase OTUB1. Our results showed that circSCD1 was upregulated in breast cancer cell lines and promoted cell viability and colony formation. Knockdown of circSCD1 increased MDA and ROS levels, decreased GSH levels, and enhanced ferroptosis in breast cancer cells. In vivo, circSCD1 knockdown significantly reduced tumor size and weight, while its overexpression enhanced tumor growth. Mechanistically, circSCD1 interacted with OTUB1 to inhibit the ubiquitination and degradation of SCD1 protein, thereby stabilizing its expression. Rescue experiments demonstrated that SCD1 overexpression partially reversed the effects of circSCD1 knockdown on cell proliferation and ferroptosis. Our findings suggest that circSCD1 plays a crucial role in promoting breast cancer cell growth and inhibiting ferroptosis by regulating SCD1 protein stability. Targeting the circSCD1/OTUB1/SCD1 axis may provide a potential therapeutic strategy for breast cancer treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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高影响因子
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2025
·Vol. 123
·期 1
·e2504904123
·
IF 9.1
Yudong Lin,Ruyue Wang,Fan Li,Zeyi Lu,Wenqin Luo,Haohua Lu,Zhehao Xu,Chang Xu,Yi Lu,Ziwei Zhu,Yang Li,Xudong Mao,Liqun Xia,Xiaojing Yu,Wenjing Su,Lifeng Ding,Gonghui Li
Androgen receptor (AR) signaling is essential for prostate cancer (PCa) cell growth and remains a key therapeutic target in castration-resistant PCa (CRPC). While circular RNAs (circRNAs) are increasingly recognized as important regulatory molecules, their roles in AR signaling during PCa progression remain poorly understood. This study identified circUTRN, an AR-inhibited circRNA that is upregulated following neoadjuvant hormonal therapy and downregulated in PCa tissues. circUTRN inhibits proliferation in both castration-sensitive and castration-resistant PCa. Mechanistically, circUTRN binds to acetyl-CoA carboxylase 1 (ACC1) and impairs the activity through both phosphorylation-dependent and independent pathways, thereby disturbing de novo fatty acid synthesis. The dynamic relation between circUTRN and ACC1 expression during PCa progression from treatment-naïve to therapeutic-resistant states highlights the metabolic vulnerability of fatty acid synthesis. Notably, we developed nanoparticles to deliver circUTRN in combination with AR signaling inhibitors (ARSIs). This approach effectively suppressed CRPC xenograft tumor growth, even in models resistant to next-generation ARSIs. This study reveals an AR-regulated circRNA involved in PCa progression and suggests a potential therapeutic strategy for treatment-resistant PCa.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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非编码RNA研究
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治疗开发
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PubMed
高影响因子
Bioengineered
·
2021
·
IF 3.269
Yute Sun,Zuoqiong Hou,Binlin Luo,Chujun Li,Jinfang Liu,Jianlan Liu,Jian Tang,Gang Yao
To identify how circular RNA circRNA_0082835 impacts melanoma cells and lymphatic metastasis to observe whether it exerts effects through its action mechanism of sponging microRNA miR-429. Clinical baseline information was collected, and clinical samples were used for detection on circRNA_0082835 and EZH2. The expression of circRNA_0082835, EZH2, and miR-429 was detected by quantitative real-time PCR (RT-qPCR). Cell proliferation was tested with cell counting kit-8 (CCK-8). Flow cytometry was applied to examination of cell cycle levels. Cell invasion and migration were observed by transwell and wound healing. The expression of Wnt/β-catenin pathway, cell cycle and epithelial–mesenchymal transition (EMT) marker proteins was analyzed by western blot. Dual-luciferase determined the binding of miR-429 and circ_0082835. As a result, the expression of circRNA_0082835 was increased and that of miR-429 was decreased with the increase in lymphatic metastasis level. CircRNA_0082835 expression was downregulated by circ_0082835 interference, upregulated by EZH2 interference and also downregulated after transfection of both shRNA-circ_0082835 and shRNA-EZH2. Inhibiting circ_0082835 and EZH2 suppressed the proliferation, invasion and migration, regulated the cell cycle levels, inhibited Wnt/β-catenin and attenuated EMT in melanoma cells. Inhibition of circ_0082835 and/or EZH2 elevated miR-429 expression. The binding among miR-429 and circ_0082835 was verified. MiR-429 inhibitor reversed the effect of circ_0082835 interference while having no significant impact on EZH2. In conclusion, circRNA_0082835 sponges miR-429 to affect the anti-tumor effect of miR-429 in primary melanoma and lymphatic metastasis.
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高影响因子
Journal of Zhejiang University-SCIENCE B
·
2025
·Vol. 26
·期 12
·1172
·
IF 4.9
Wei HU,Tianyi FEI,Zhichao LIU,Yude DING,Mengfei YU,Fan YANG,Feiya ZHAO
The pathological microenvironment of osteoporosis poses a substantial clinical challenge for bone defect regeneration. Through single-cell RNA-sequencing (scRNA-seq) analysis, we identified a reactive oxygen species (ROS)-overloading osteoblast subpopulation as a critical pathological feature of osteoporotic niches. Guided by scRNA-seq analysis, we engineered a microenvironment-adaptive hydrogel system through precise integration of antioxidant curcumin-encapsulated zeolitic imidazolate framework-8 nanoparticles (CCM@ZIF-8 NPs) within photo-crosslinkable alginate methacrylate (AlgMA) hydrogel (AlgMA/CCM@ZIF-8). This engineered design exhibited dual functions: effectively scavenging ROS in bone marrow-derived mesenchymal stem cells (BMSCs) while simultaneously suppressing osteoclast differentiation. The osteo-regenerative superiority of the AlgMA/CCM@ZIF-8 nanocomposite hydrogel was conclusively demonstrated in bone defect models of osteoporotic mice. This scRNA-seq-informed engineering strategy offers a promising approach for developing pathophysiology-adapted biomaterials to promote regenerative repair in osteoporotic bone defects. 骨质疏松症的特殊病理微环境为骨缺损再生带来了巨大的临床挑战。通过单细胞转录组测序技术本研究发现活性氧（ROS）过载的成骨细胞亚群是骨质疏松微环境的关键病理特征。在此基础上，本研究将姜黄素包裹的沸石咪唑酯框架-8（CCM@ZIF-8）纳米颗粒整合到光交联甲基丙烯酰化海藻酸盐（AlgMA）水凝胶中，构建了一种微环境自适应水凝胶系统（AlgMA/CCM@ZIF-8）。该设计展现出有效清除骨髓间充质干细胞ROS过载和抑制破骨细胞分化的双重功能，且其骨再生优势在骨质疏松小鼠骨缺损模型中得到明确验证。这种基于单细胞转录组测序分析的工程策略为开发适配病理生理学特征的生物材料以促进骨质疏松性骨缺损的再生修复，创立了极具前景的新方法。
研究领域:
生物医学工程
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再生医学
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骨骼生物学
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纳米材料
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转录组学
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高影响因子
Biomarker Research
·
2026
·
IF 14.6
Ruixin Wu,Licheng Zhang,Peter JihCheng Wong,Chunming Sun,Yuan Feng,Xiaoyu Wang,Minjie Fu,Jinsen Zhang,Fufang Qiu,Xi Chen,Zhen Fan,Minfeng Shu,Wei Hua
IDH mutant gliomas, driven by the oncometabolite 2-hydroxyglutarate (2-HG), are associated with profound neurological morbidity and premature mortality. To address the unmet therapeutic needs, we investigated the mechanistic interplay between MTHFD2-driven one-carbon metabolism and ferroptosis susceptibility in these tumors. Our findings revealed that MTHFD2 upregulation, mediated through loss of m5C modification in chromatin associated RNAs (caRNAs)-establishes a metabolic vulnerability to ferroptosis. Crucially, we identified TAF15 as a pivotal RNA-binding protein that orchestrates the spatial recruitment of TET2 by bridging NSUN5-mediated RNA m5C methylation. Therapeutically, combinatorial targeting of MTHFD2 with its selective inhibitor and the hypomethylating agent decitabine induced ferroptosis in patient-derived IDH-mut glioma organoids, demonstrating potent ferroptosis activation. This work delineates an RNA epitranscriptomic-metabolism axis in glioma pathogenesis and provides a translational roadmap for exploiting metabolic dependencies in IDH-driven malignancies. CLINICAL TRIAL NUMBER: Not applicable.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2026
·
IF 5
Guihong Li,Ting Lei,Erpeng Liu,Jing Shen,Dun Liu,Xuqiang Zhu
USP53 upregulation is identified as an independent risk factor for GBM progression. • USP53 upregulation is associated with poor prognosis of GBM patients. • USP53 promotes cell growth and the tumorigenicity of GBM cells. • USP53 removes ubiquitination from ALKBH5 and enhances its stability. • ALKBH5 removes the m6A modification of TERT and increases its RNA stability. Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. Deubiquitinating enzyme ubiquitin-specific peptidase 53 (USP53), known to enhance the stability of downstream proteins, exhibits distinct functions in different tumors. The function of USP53 in GBM progression remains unclear. Analysis of GSE104267 and GSE4290 datasets revealed significant USP53 upregulation in GBM tissues, a finding confirmed by TCGA data comparing GBM ( n = 163) with normal brain tissues ( n = 207). In univariate and multivariate cox regression analysis, USP53 was identified as an independent risk factor (univariate, hazard ratio (HR) =1.5357, p = 0.0229; multivariate, HR =1.4851, p = 0.0385) for GBM progression. Patients with high expression of USP53 had worse prognosis compared to those with low expression of USP53. Functionally, USP53 knockdown potently inhibited proliferation and induced apoptosis in LN229 and A172 cells in vitro and attenuated tumorigenicity of LN229 cells in vivo . Conversely, forced expression of USP53 had a carcinogenic effect. Mechanistically, USP53 targeted ALKB homolog 5 (ALKBH5) for deubiquitination, thereby stabilizing the protein and prolonging its half-life. Restoring ALKBH5 expression rescued the proliferative deficit in USP53-silenced LN229 cells. Telomerase catalytic subunit telomerase reverse transcriptase (TERT) was identified as a downstream effector of the USP53/ALKBH5 axis, where ALKBH5 upregulated TERT RNA expression by erasing m6A modifications at position 1989 bp on TERT mRNA. Collectively, those observations demonstrate that USP53/ALKBH5 axis drives GBM progression by targeting TERT, indicating that USP53/ALKBH5 axis may serve as a potential therapeutic target for GBM. Download: Download high-res image (229KB) Download: Download full-size image
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ACS Synthetic Biology
·
2026
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IF 4.5
Junpeng Jia,Yifeng Wei,Yating Li,Jason Tan,Yiling Hu,Yang Tong,Xinan Jiao,Yan Zhang,Yan Zhou
2-amino-deoxyadenosine (dZ) occurs naturally in certain bacteriophage genomes, where it replaces deoxyadenosine, forming three hydrogen bonds with thymidine. This noncanonical deoxyribonucleoside underlies the unique biophysical properties of dZ-DNA. Its corresponding ribonucleoside has been introduced to RNA to form Z-modified RNA, with promising applications in vaccine production and biomedicine. Unlike dZ-DNA, Z-modified RNA has only been synthesized in vitro, which required the addition of chemically synthesized 2-amino-adenosine triphosphate (ZTP) as a precursor. Here, we describe enzyme engineering studies on dZMP–succinate-synthetase (PurZ), a key enzyme in the bacteriophage dZ-DNA biosynthetic pathway that natively catalyzes the conversion of deoxyguanosine monophosphate (dGMP) to dZMP–succinate. Through site-saturation mutagenesis, we generated mutants with altered substrate specificity, capable of catalyzing the conversion of GMP to ZMP–succinate. We further demonstrated that these mutants, in combination with bacterial adenylosuccinate lyase, guanylate kinase and nucleoside diphosphate kinase, efficiently convert GMP to ZTP, marking a critical step in developing a biosynthetic pathway for Z-modified RNA, and enabling enzymatic synthesis of ZTP on a semipreparative scale. Our work provides the basis for further research on the impacts of Z-modified RNA in living organisms, and supports the cost-effective production of Z-modified RNA vaccines and therapeutics.
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高影响因子
ANTIVIRAL RESEARCH
·
2026
·
IF 4.3
Ting Zhang,Zi-Ling Wang,Xi-Ya Li,Rong-Hua Luo,Lu-Xi Zhang,Hong-Yi Zheng,Si-Dong Xiong,Wen-Lan Yang,Yong-Tang Zheng
The continuous emergence of new SARS-CoV-2 variants limits the effectiveness of current vaccines and monoclonal antibodies, highlighting the urgent need for complementary antiviral strategies. Targeting host proteins that are exploited by the virus represents a promising approach to achieve broad-spectrum inhibition. Given the recently established proviral role of METTL3-dependent RNA m 6 A modification in SARS-CoV-2 replication, we conducted a structure-based virtual screening to repurpose compounds with acceptable safety profiles. Subsequent biochemical validation identified onvansertib and vilazodone as direct METTL3 binders and potent inhibitors of its methyltransferase activity. Notably, both compounds effectively suppressed the replication of ancestral SARS-CoV-2 and Omicron BA.2 variant in vitro . Mechanistically, each compound potentially enhanced the innate antiviral response of the host and repressed the expression of viral entry-associated host factors during infection; this observation is consistent with the established proviral role of METTL3. In summary, these findings not only substantiate METTL3 as a viable antiviral target but also lay the foundation for further research on the therapeutic potential of onvansertib and vilazodone against COVID-19.
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TRENDS IN BIOTECHNOLOGY
·
2026
·
IF 16.6
Shichao Li,Ting Gao,Yinhao Wang,Qingjing He,Huiling Ma,Hui Ye,Yuqing Shen,Yukai Wang,Yujue Wang,Xiaoqing Li,Shaocong Fang,Qidi Chen,Qi Liu,Gangyu Sun,Huhu Xin,Jianzhuang Xue,Sicun Liu,Min Zhu,Wenqing Xu,Zhizhi Wang,Jiawei Shao,Mingqi Xie
In this study, we describe a rationally designed light-inducible RNA-releasing protein (LIRP) capable of inhibiting mRNA translation in the dark while permitting gene expression upon exposure to blue or ambient light. This LIRP-dependent gene switch is compatible with various delivery routes of gene- and cell-based therapy, such as subcutaneous implantation of microencapsulated light-sensitive cells or expression in various light-accessible body sites using single adeno-associated virus (AAV) vectors. To exemplify a gene therapy approach that directly harnesses ambient light as a natural illumination source to induce therapeutic action, we show how intradermal delivery of AAV2 vectors carrying a LIRP-regulated gene switch controlling murine thymic stromal lymphopoietin expression was effective in enabling light-dependent prevention and treatment of diet-induced obesity. To describe another therapeutic scenario, we engineered AAV2 vectors for LIRP-dependent expression of Vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinal neovascular diseases. Upon intravitreal delivery into mice suffering from wet macular degeneration, VEGF inhibitors were constantly produced when animals were exposed to daylight, but therapeutic actions could be flexibly interrupted either by exposure to dark environments or by administration of a selective blue light filter at any point in time. When compared to conventional treatment strategies based on constitutive VEGF inhibition over the course of 3 months, we show that a regulated gene therapy approach through LIRP-dependent optogenetics was advantageous in maintaining a normal retina thickness. This work not only provides a valuable addition to the optogenetic toolbox but also offers a perspective to translate light-dependent gene switches toward therapeutic usage.
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高影响因子
Translational Cancer Research
·
2026
·Vol. 15
·期 2
·90
·
IF 2.1
Zhao Yubo,Zhang Digun,Zheng Hongqun,Chen Xuejian,Xu Lishan
Background N6-methyladenosine (m6A) regulators are involved in hepatocellular carcinoma (HCC) development. However, the functions of m6A regulators in HCC have not yet been elucidated. This study aimed to evaluate the potential of m6A methylation regulators as biomarkers and immunotherapeutic targets in HCC. Methods RNA sequencing data were obtained from publicly available databases including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Bioinformatics analysis was conducted, including Kaplan-Meier (KM) survival analysis, univariate and multivariate Cox regression, receiver operating characteristic (ROC) curve analysis and immune-related signatures were assessed using single-sample gene set enrichment analysis (ssGSEA) and drug sensitivity prediction was performed to identify potential small-molecule compounds. In vitro , small interfering RNA (siRNA)-mediated knockdown of selected m6A regulators was performed in three HCC cell lines (HepG2, HuH7 and MHCC-97H). Quantitative polymerase chain reaction (qPCR) and Western blot (WB) were subsequently conducted to validate gene expression changes. Additionally, WB was performed after treatment with candidate drugs to evaluate their functional impact. Results The five upregulated m6A regulators in HCC, KIAA1429, METTL3, PRRC2A, RBMX, and ZC3H3, were related to worse outcomes in HCC. ROC curves showed that m6A regulators could accurately distinguish between normal and HCC tumor tissues. Furthermore, differential m6A regulator expression was affected by immune infiltration. In advanced HCC patients, m6A regulators were important in determining clinical outcomes. Drug response analysis demonstrated m6A regulators as potential therapeutic agents that could be used as guidance for patients with HCC. PCR and WB analysis showed that m6A regulators could act on immune-related sites, interact with immune tolerance, and inhibit it. Conclusions This study indicates that KIAA1429, METTL3, PRRC2A, RBMX, and ZC3H3 may be potential immunotherapeutic targets and biomarkers in HCC.
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