{"title":"The regulatory roles of RNA-binding proteins in the tumour immune microenvironment of gastrointestinal malignancies.","authors":"Dongqi Li, Xiangyu Chu, Weikang Liu, Yongsu Ma, Xiaodong Tian, Yinmo Yang","doi":"10.1080/15476286.2024.2440683","DOIUrl":"10.1080/15476286.2024.2440683","url":null,"abstract":"<p><p>The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m<sup>6</sup>A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":"22 1","pages":"1-14"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882916","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}
{"title":"A lineage 1 branch porcine reproductive and respiratory syndrome virus live vaccine candidate provides broad cross-protection against HP-like PRRSV in piglets.","authors":"Chao Li, Jinhao Li, Bangjun Gong, Hu Xu, Zhenyang Guo, Lirun Xiang, Siyu Zhang, Qi Sun, Jing Zhao, Menglin Zhang, Yan-Dong Tang, Chaoliang Leng, Jianan Wu, Qian Wang, Jinmei Peng, Guohui Zhou, Huairan Liu, Tongqing An, Xuehui Cai, Zhi-Jun Tian, Hongliang Zhang","doi":"10.1080/21505594.2025.2451754","DOIUrl":"https://doi.org/10.1080/21505594.2025.2451754","url":null,"abstract":"<p><p>Multiple porcine reproductive and respiratory syndrome virus (PRRSV) subtypes coinfect numerous pig farms in China, and commercial PRRSV vaccines offer limited cross-protection against heterologous strains. Our previous research confirmed that a PRRSV lineage 1 branch attenuated live vaccine (SD-R) provides cross-protection against HP-PRRSV, NADC30-like PRRSV and NADC34-like PRRSV. HP-PRRSV has undergone significant genetic variation following nearly two decades of evolution and has transformed into a subtype referred to as HP-like PRRSV, which also exhibits high pathogenicity. The effectiveness of immunising piglets with the SD-R strain to provide protection against infection with HP-like PRRSV remains uncertain. In the present study, we evaluated the protective effects of SD-R vaccine strains on DLF-challenged piglets. The results revealed that piglets challenged with DLF presented clinical symptoms such as continuous high fever and an obvious decrease in daily weight gain. Importantly, the piglets immunised with SD-R exhibited notable reductions in pathological damage, especially of decreases in DLF-induced thymic atrophy. Moreover, the serum of SD-R-immunised piglets strongly neutralised DLF, and the number of SD-R-vaccinated piglets demonstrating viraemia was greatly reduced. These results suggest that the PRRSV lineage 1 branch live vaccine candidate provides broad cross-protection against HP-like PRRSV in piglets.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2451754"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VirulencePub Date : 2025-12-01Epub Date: 2025-01-13DOI: 10.1080/21505594.2025.2450462
Ye Huang, Yuan Huang, Zhiping Wu, Ziyue Fan, Fanglin Zheng, Yang Liu, Xinping Xu
{"title":"Characterization and genomic insights into bacteriophages Kpph1 and Kpph9 against hypervirulent carbapenem-resistant <i>Klebsiella pneumoniae</i>.","authors":"Ye Huang, Yuan Huang, Zhiping Wu, Ziyue Fan, Fanglin Zheng, Yang Liu, Xinping Xu","doi":"10.1080/21505594.2025.2450462","DOIUrl":"https://doi.org/10.1080/21505594.2025.2450462","url":null,"abstract":"<p><p>The increasing incidence of infections attributed to hypervirulent carbapenem-resistant <i>Klebsiella pneumoniae</i> (Hv-CRKp) is of considerable concern. Bacteriophages, also known as phages, are viruses that specifically infect bacteria; thus, phage-based therapies offer promising alternatives to antibiotic treatments targeting Hv-CRKp infections. In this study, two isolated bacteriophages, Kpph1 and Kpph9, were characterized for their specificity against the Hv-CRKp <i>K. pneumoniae</i> NUHL30457 strain that possesses a K2 capsule serotype. Both phages exhibit remarkable environmental tolerance, displaying stability over a range of pH values (4-11) and temperatures (up to 50°C). The phages demonstrate potent antibacterial and antibiofilm efficacy, as indicated by their capacity to inhibit biofilm formation and to disrupt established biofilms of Hv-CRKp. Through phylogenetic analysis, it has been revealed that Kpph1 belongs to the new species of <i>Webervirus</i> genus, and Kpph9 to the <i>Drulisvirus</i> genus. Comparative genomic analysis suggests that the tail fiber protein region exhibits the greatest diversity in the genomes of phages within the same genus, which implies distinct co-evolution histories between phages and their corresponding hosts. Interestingly, both phages have been found to contain two tail fiber proteins that may exhibit potential depolymerase activities. However, the exact role of depolymerase in the interaction between phages and their hosts warrants further investigation. In summary, our findings emphasize the therapeutic promise of phages Kpph1 and Kpph9, as well as their encoded proteins, in the context of research on phage therapy targeting hypervirulent carbapenem-resistant <i>Klebsiella pneumoniae</i>.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2450462"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correlation analysis of key genes and immune infiltration in visceral adipose tissue and subcutaneous adipose tissue of patients with type 2 diabetes in women.","authors":"Qian Shi, Yongxin Li, Chunyan Liu, Mengjie Liang, Hefei Zha, Xin Zhang, Fuchun Zhang","doi":"10.1080/21623945.2024.2442419","DOIUrl":"https://doi.org/10.1080/21623945.2024.2442419","url":null,"abstract":"<p><p>Immune cell infiltration into adipose tissue (AT) is a key factor in type 2 diabetes (T2DM). However, research on the impact of fat distribution on immune cells and immune responses in women is still lacking. This study used enrichment, protein-protein interaction network, immune cell infiltration, and correlation analysis to compare the similarities and differences between the transcriptome data of visceral AT (VAT) and subcutprotein-proteinaneous AT (SAT) obtained from the omprehensive database of gene expression in women with non-T2DM and T2DM. DEGs with the same biological function in two types of ATs often exhibited different expression trends. SharedVAT-specific and SAT-specific hub genes were mainly associated with transcription factors, monocyte-macrophage markers, and chemokines, respectively. Immune cells affected by both AT types included monocytes, granulocytes, T and B lymphocytes, and NK cells. VAT affected more immune cells, mainly myeloid cells. Shared hub genes in VAT correlated positively with M1 macrophages, suggesting pro-inflammatory effects, while those in SAT correlated negatively with M1 macrophages and lymphocytes, suggesting anti-inflammatory effects. This study provides a theoretical basis for further understanding the correlation between AT and T2DM in women.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":"14 1","pages":"2442419"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VirulencePub Date : 2025-12-01Epub Date: 2024-12-23DOI: 10.1080/21505594.2024.2444686
Pengpeng Xiao, Yujia Hao, Yuge Yuan, Wenzhou Ma, Yiquan Li, He Zhang, Nan Li
{"title":"Emerging West African Genotype Chikungunya Virus in Mosquito Virome.","authors":"Pengpeng Xiao, Yujia Hao, Yuge Yuan, Wenzhou Ma, Yiquan Li, He Zhang, Nan Li","doi":"10.1080/21505594.2024.2444686","DOIUrl":"https://doi.org/10.1080/21505594.2024.2444686","url":null,"abstract":"<p><p>We studied the viromes of three dominant mosquito species in Wenzhou, a coastal city in Zhejiang Province, using metavirome sequencing, with 18 viral families identified. Viral sequences were verified by RT-PCR. The JEV E gene was most closely related to the 1988 Korean strain. DENV sequences were most closely related to the 1997 Australian strain. CHIKV-E1-1 was most closely related to the 1983 Senegal strain and belonged to West African genotype CHIKV. Remarkably, this is the first time that a West African genotype of CHIKV has been detected in Zhejiang Province. Mutations in the CHIKV-E1-1 protein A226V may increase infectivity in <i>Ae. albopictus</i>. Three non-conservative mutations of CHIKV-E1-1 (D45H, D70H and V290D) may have an impact on the function. In conclusion, our study reveals the diversity of mosquito-borne viruses and potential emerging outbreaks in the southeast coastal region of China, providing new perspectives for mining the ecological characterization of other important arboviruses.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2444686"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2024-12-26DOI: 10.1080/15476286.2024.2442856
Minjie Zhang, Zhipeng Lu
{"title":"tRNA modifications: greasing the wheels of translation and beyond.","authors":"Minjie Zhang, Zhipeng Lu","doi":"10.1080/15476286.2024.2442856","DOIUrl":"https://doi.org/10.1080/15476286.2024.2442856","url":null,"abstract":"<p><p>Transfer RNA (tRNA) is one of the most abundant RNA types in cells, acting as an adaptor to bridge the genetic information in mRNAs with the amino acid sequence in proteins. Both tRNAs and small fragments processed from them play many nonconventional roles in addition to translation. tRNA molecules undergo various types of chemical modifications to ensure the accuracy and efficiency of translation and regulate their diverse functions beyond translation. In this review, we discuss the biogenesis and molecular mechanisms of tRNA modifications, including major tRNA modifications, writer enzymes, and their dynamic regulation. We also summarize the state-of-the-art technologies for measuring tRNA modification, with a particular focus on 2'-O-methylation (Nm), and discuss their limitations and remaining challenges. Finally, we highlight recent discoveries linking dysregulation of tRNA modifications with genetic diseases.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":"22 1","pages":"1-25"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897124","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}
Redox ReportPub Date : 2025-12-01Epub Date: 2024-12-31DOI: 10.1080/13510002.2024.2435241
Ying Wang, Xueying Yu, Fenyong Sun, Yan Fu, Tingting Hu, Qiqing Shi, Qiuhong Man
{"title":"METTL14 Mediates <i>Glut3</i> m6A methylation to improve osteogenesis under oxidative stress condition.","authors":"Ying Wang, Xueying Yu, Fenyong Sun, Yan Fu, Tingting Hu, Qiqing Shi, Qiuhong Man","doi":"10.1080/13510002.2024.2435241","DOIUrl":"https://doi.org/10.1080/13510002.2024.2435241","url":null,"abstract":"<p><strong>Objectives: </strong>Bone remodeling imbalance contributes to osteoporosis. Though current medications enhance osteoblast involvement in bone formation, the underlying pathways remain unclear. This study was aimed to explore the pathways involved in bone formation by osteoblasts, we investigate the protective role of glycolysis and N6-methyladenosine methylation (m6A) against oxidative stress-induced impairment of osteogenesis in MC3T3-E1 cells.</p><p><strong>Methods: </strong>We utilized a concentration of 200 μM hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) to establish an oxidative damage model of MC3T3-E1 cells. Subsequently, we examined the alterations in the m6A methyltransferases (METTL3, METTL14), glucose transporter proteins (GLUT1, GLUT3) and validated m6A methyltransferase overexpression in vitro and in an osteoporosis model. The osteoblast differentiation and osteogenesis-related molecules and serum bone resorption markers were measured by biochemical analysis, Alizarin Red S staining, Western blot and ELISA.</p><p><strong>Results: </strong>H<sub>2</sub>O<sub>2</sub> treatment inhibited glycolysis and osteoblast differentiation in MC3T3-E1 cells. However, when METTL14 was overexpressed, these changes induced by H<sub>2</sub>O<sub>2</sub> could be mitigated. Our findings indicate that METTL14 promotes GLUT3 expression via YTHDF1, leading to the modulation of various parameters in the H<sub>2</sub>O<sub>2</sub>-induced model. Similar positive effects of METTL14 on osteogenesis were observed in an ovariectomized mouse osteoporosis model.</p><p><strong>Discussion: </strong>METTL14 could serve as a potential therapeutic approach for enhancing osteoporosis treatment.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"30 1","pages":"2435241"},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The highly pathogenic strain of porcine deltacoronavirus disrupts the intestinal barrier and causes diarrhea in newborn piglets.","authors":"Xin Yao, Wei-Hong Lu, Wen-Ting Qiao, Yu-Qian Zhang, Bao-Ying Zhang, Hui-Xin Li, Jin-Long Li","doi":"10.1080/21505594.2024.2446742","DOIUrl":"https://doi.org/10.1080/21505594.2024.2446742","url":null,"abstract":"<p><p>Porcine deltacoronavirus (PDCoV) is increasingly prevalent in newborn piglets with diarrhea. With the development of research on the virus and the feasibility of PDCoV cross-species transmission, the biosafety and the development of pig industry have been greatly affected. In this study, a PDCoV strain CH/LNFX/2022 was isolated from diarrheal newborn piglets at a farm in China. A genome-wide based phylogenetic analysis suggests that 97.5% to 99.2% homology existed in the whole genomes of other strains. Five amino acid mutations are seen for the first time in the S protein. By constructing 3D models, it was found that the S1-NTD/CTD and S2-HR-C regions produced structural alterations. Protein functional analysis showed that the structural changes of the three regions changed the epitope of S protein, the O-GalNAc glycosylation site and the 3C-like protease cleavage site. In addition, oral administration of 10<sup>7</sup> TCID<sub>50</sub> CH/LNFX/2022 to newborn piglets successfully reproduced obvious clinical signs of piglets, such as diarrhea and dehydration. Meanwhile, PDCoV antigen was detected by immunofluorescence in the small intestine, and microscopic lesions and intestinal mucosal barrier destruction were detected by histological observation and scanning electron microscopy. Our study confirmed that porcine coronavirus strains increased pathogenicity through evolution, damaged the intestinal barrier of newborn piglets, and caused diarrhea in pigs. This study provided the candidate strains and theoretical basis for establishing the prevention and control system of vaccine and diagnostic methods for piglet diarrhea.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2446742"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Redox ReportPub Date : 2025-12-01Epub Date: 2024-12-26DOI: 10.1080/13510002.2024.2445398
Amira K Eltokhy, Rehab Ahmed Ahmed El-Shaer, Omnia Safwat El-Deeb, Eman E Farghal, Rowida Raafat Ibrahim, Rasha Elesawy, Marwa Mahmoud Awad, Radwa Ismail, Shaimaa M Motawea, Doaa Shatat, Yasser Mostafa Hafez, Hend Ahmed El Hanafy, Marwa Mohamed Atef
{"title":"Synergistic effects of AgNPs and zileuton on PCOS via ferroptosis and inflammation mitigation.","authors":"Amira K Eltokhy, Rehab Ahmed Ahmed El-Shaer, Omnia Safwat El-Deeb, Eman E Farghal, Rowida Raafat Ibrahim, Rasha Elesawy, Marwa Mahmoud Awad, Radwa Ismail, Shaimaa M Motawea, Doaa Shatat, Yasser Mostafa Hafez, Hend Ahmed El Hanafy, Marwa Mohamed Atef","doi":"10.1080/13510002.2024.2445398","DOIUrl":"https://doi.org/10.1080/13510002.2024.2445398","url":null,"abstract":"<p><strong>Background: </strong>The most prevalent endocrine disorder affecting women is PCOS. Programmed death of ovarian cells has yet to be elucidated. Ferroptosis is a kind of iron-dependent necrosis featured by significantly Fe<sup>+2</sup>-dependent lipid peroxidation. The ongoing study aimed to reinforce fertility by combining therapy with AgNPs and (Zileuton) in PCOS rats' model.</p><p><strong>Methods: </strong>The study included 75 adult female rats divided into 5 groups; control, PCOS, PCOS treated with AgNPs, PCOS treated with Zileuton, and PCOS group treated with AgNPs and Zileuton. The study investigated the anti-ferroptotic, anti-inflammatory, antioxidant, antiapoptotic, histopathological and immunohistochemical examinations of COX-2 and VEGF.</p><p><strong>Results: </strong>The combination of AgNPs and Zileuton showed significant reduction of inflammatory mediators (IL-6, TNF-α, NFk-B) compared with diseased group (<i>P</i>-<i>value</i> < 0.05), regression of ferroptosis marks (Panx1 and TLR4 expression, Fe<sup>+2</sup> levels) compared with diseased group (<i>P</i>-<i>value</i> < 0.05), depression of apoptotic marker caspase 3 level compared with diseased animals (<i>P</i>-value < 0.05), depression of MDA level, elevation of HO-1, GPx4 activity, and reduction of Cox2 and VEGF as compared with the diseased, AgNPs or zileuton-treated groups (<i>P</i>-value < 0.05).</p><p><strong>Conclusion: </strong>The study showed that the combination of AgNPs and zileuton guards against, inflammation, apoptosis, and ferroptosis in PCO.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"30 1","pages":"2445398"},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
VirulencePub Date : 2025-12-01Epub Date: 2024-12-28DOI: 10.1080/21505594.2024.2445238
Xia Chen, Ming Kong, Chunxi Ma, Manyu Zhang, Zenglei Hu, Min Gu, Xiaoquan Wang, Ruyi Gao, Shunlin Hu, Yu Chen, Xiaowen Liu, Daxin Peng, Xiufan Liu, Jiao Hu
{"title":"The PA-X host shutoff site 100 V exerts a contrary effect on viral fitness of the highly pathogenic H7N9 influenza A virus in mice and chickens.","authors":"Xia Chen, Ming Kong, Chunxi Ma, Manyu Zhang, Zenglei Hu, Min Gu, Xiaoquan Wang, Ruyi Gao, Shunlin Hu, Yu Chen, Xiaowen Liu, Daxin Peng, Xiufan Liu, Jiao Hu","doi":"10.1080/21505594.2024.2445238","DOIUrl":"https://doi.org/10.1080/21505594.2024.2445238","url":null,"abstract":"<p><p>Several viruses, including influenza A virus (IAV), encode viral factors to hijack cellular RNA biogenesis processes to direct the degradation of host mRNAs, termed \"host shutoff.\" Host shutoff enables viruses to simultaneously reduce antiviral responses and provides preferential access for viral mRNAs to cellular translation machinery. IAV PA-X is one of these factors that selectively shuts off the global host genes. However, the specific role of PA-X host shutoff activity in viral fitness of IAV remains poorly understood. Herein, we successfully mapped PA-X 100 V as a novel site important for host shutoff of the H7N9 and H5N1 viruses. By analysing the polymorphism of this residue in various subtype viruses, we found that PA-X 100 was highly variable in H7N9 viruses. Structural analysis revealed that 100 V was generally close to the PA-X endonuclease active site, which may account for its host shutoff activity. By generating the corresponding mutant viruses derived from the parental H7N9 virus and the PA-X-deficient H7N9 virus, we determined that PA-X 100 V significantly enhanced viral fitness in mice while diminishing viral virulence in chickens. Mechanistically, PA-X 100 V significantly increased viral polymerase activity and viral replication in mammalian cells. Furthermore, PA-X 100 V highly blunted the global host response in 293T cells, particularly restraining genes involved in energy metabolism and inflammatory response. Collectively, our data provided information about the intricate role of the PA-X host shutoff site in regulating the viral fitness of the H7N9 influenza virus, which furthers our understanding of the complicated pathogenesis of the influenza A virus.</p>","PeriodicalId":23747,"journal":{"name":"Virulence","volume":"16 1","pages":"2445238"},"PeriodicalIF":5.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}