{"title":"LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants.","authors":"Zhenfei Bi, Wenyan Ren, Hao Zeng, Yuanyuan Zhou, Jian Liu, Zimin Chen, Xindan Zhang, Xuemei He, Guangwen Lu, Yuquan Wei, Xiawei Wei","doi":"10.1111/cpr.70060","DOIUrl":"https://doi.org/10.1111/cpr.70060","url":null,"abstract":"<p><p>Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70060"},"PeriodicalIF":5.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiyang Wang, Xinyi Du, Chenxi Duan, Miaomiao Wang, Ying Zhu, Lihua Wang, Jun Hu, Yanhong Sun
{"title":"Regulating the Plasticity of Hippocampal Neurons via Electroacupuncture in Depression Model Mice.","authors":"Yiyang Wang, Xinyi Du, Chenxi Duan, Miaomiao Wang, Ying Zhu, Lihua Wang, Jun Hu, Yanhong Sun","doi":"10.1111/cpr.70057","DOIUrl":"https://doi.org/10.1111/cpr.70057","url":null,"abstract":"<p><p>Effective treatment of depression poses a major clinical challenge, accompanied by considerable social and emotional burdens. Electroacupuncture, a non-pharmacological modality derived from traditional Chinese medicine, offers a promising alternative for depression treatment due to its safety and efficacy. However, its underlying molecular mechanisms remain unclear. In this study, a corticosterone-induced depression model in C57BL/6 mice was employed and electroacupuncture was applied to stimulate at Zusanli (ST36) acupoint. The results demonstrated that electroacupuncture effectively alleviated depression-like symptoms and restored the structural morphology and plasticity of neurons in the hippocampal CA1 region. Further analysis revealed a significant upregulation of brain-derived neurotrophic factor (BDNF) and β-type calmodulin-dependent protein kinase II (CaMKIIβ), which are associated with neuronal plasticity regulatory pathways. This study elucidates the potential molecular mechanisms by which electroacupuncture alleviates depression through the regulation of neuroplasticity, providing an experimental basis for its clinical application.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70057"},"PeriodicalIF":5.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Deciphering the Immunomodulatory Function of GSN<sup>+</sup> Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis.","authors":"Shan Li, Xinwei Zhou, Haoqian Feng, Kangbo Huang, Minyu Chen, Mingjie Lin, Hansen Lin, Zebing Deng, Yuhang Chen, Wuyuan Liao, Zhengkun Zhang, Jinwei Chen, Bohong Guan, Tian Su, Zihao Feng, Guannan Shu, Anze Yu, Yihui Pan, Liangmin Fu","doi":"10.1111/cpr.70062","DOIUrl":"https://doi.org/10.1111/cpr.70062","url":null,"abstract":"<p><p>The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN<sup>+</sup> iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN<sup>+</sup> iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN<sup>+</sup> iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN<sup>+</sup> iCAFs and CD8<sup>+</sup> Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN<sup>+</sup> iCAFs and CD8<sup>+</sup> exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8<sup>+</sup> T cells, downregulation of GSN on CAFs drives CD8<sup>+</sup> T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70062"},"PeriodicalIF":5.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nano-Mediated Fluorescence Switching for Epidermal Growth Factor Receptor Detection.","authors":"Xin Fu, Yuhao Wang, Wenxin Zhang, Yuepeng Yang, Jialin Zeng, Xiaodie Li, Chengyu Feng, Bin Li, Yingying Liu, Yinan Zhang, Chao Zhang, Sicong Ma","doi":"10.1111/cpr.70063","DOIUrl":"https://doi.org/10.1111/cpr.70063","url":null,"abstract":"<p><p>Identification of the epidermal growth factor receptor (EGFR) in biological specimens is essential for cancer diagnostics, drug development and therapeutic monitoring. However, real-time techniques for accurate EGFR expression monitoring are currently limited. In this study, we report the development of a novel nano detector (Cy3-Apt<sub>EGFR</sub>@BPNSs) with the capabilities of quenching and recovery to enable visual EGFR expression analysis. Cy3-Apt<sub>EGFR</sub> is a Cy3-labelled single-stranded RNA (ssRNA) that exhibits specific binding to EGFR. Black phosphorus nanosheets (BPNSs) possess the ability to adsorb Cy3-Apt<sub>EGFR</sub> via van der Waals forces, quenching its fluorescence when combined. The detection of EGFR receptors on cancer cell surfaces prompts the release of Cy3-Apt<sub>EGFR</sub> from BPNSs, a consequence of the robust binding interaction between the receptor and aptamer, thereby leading to fluorescence reinstatement. The recovered fluorescence intensity of this detector is found to be directly correlated with EGFR expression levels in cancer cells, indicating its potential for guiding tumour diagnosis and treatment. The specificity of Cy3-Apt<sub>EGFR</sub>@BPNSs further enhances its utility in detecting EGFR. More importantly, our research demonstrates that the reduction in EGFR expression levels within cancer cells corresponds to a proportional decline in fluorescence intensity, thereby facilitating precise tracking of EGFR dynamics.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70063"},"PeriodicalIF":5.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RBM39 Promotes Base Excision Repair to Facilitate the Progression of HCC by Stabilising OGG1 mRNA.","authors":"Hongda An, Anliang Xia, Siyuan Liu, Dongjun Luo, Longpo Geng, Binghua Li, Beicheng Sun, Zhu Xu","doi":"10.1111/cpr.70059","DOIUrl":"https://doi.org/10.1111/cpr.70059","url":null,"abstract":"<p><p>Targeting base excision repair (BER) has been an attractive strategy in cancer therapeutics. RNA-binding motif protein 39 (RBM39) modulates the alternative splicing of numerous genes involved in cancer occurrence and progression. However, whether and how RBM39 regulates BER in hepatocellular carcinoma (HCC) remain unclear. Here, we found that under oxidative stress, RBM39 degradation or knockdown decreased BER efficiency in HCC cells using a well-designed BER reporter. Further assays showed that RBM39 promoted HCC cell proliferation, migration, and invasion, enhancing cell survival and inhibiting apoptosis. Mechanistically, RBM39 interacted with the mRNA of the essential glycosidase 8-oxoguanine-DNA glycosylase 1 (OGG1), thereby stabilising OGG1 mRNA. This in turn increases OGG1 expression and promotes BER efficiency in HCC. Moreover, data suggested that RBM39 degradation, combined with oxidative damage, could be more effective for HCC treatment than monotherapy, both in vitro and in xenograft mice models. Overall, we demonstrated that RBM39 regulated OGG1 stabilisation and improved BER efficiency, suggesting that combining the RBM39 degradant indisulam with the oxidising agent KBrO<sub>3</sub> could be an emerging strategy for HCC treatment.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70059"},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NSun2-Mediated tsRNAs Alleviate Liver Fibrosis via FAK Dephosphorylation.","authors":"Pengcheng Li, Sunyang Ying, Yu Zou, Xin Wang, Runxue Zhang, Cheng Huang, Moyu Dai, Kai Xu, Guihai Feng, Xin Li, Haiping Jiang, Zhikun Li, Ying Zhang, Wei Li, Qi Zhou","doi":"10.1111/cpr.70058","DOIUrl":"https://doi.org/10.1111/cpr.70058","url":null,"abstract":"<p><p>Sinusoidal capillarization - key symptoms of liver fibrosis progression - represents potential therapeutic targets. tRNA modification-mediated tRNA-derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF-1-S25 and tRF-5-V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK - crucial clinical targets. Moreover, intravenous injection of tRF-1-S25 and tRF-5-V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2-mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p-FAK pathway offers an innovative approach to treat this disease.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70058"},"PeriodicalIF":5.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Research Advances of the Autophagy-Regulated Radiosensitivity.","authors":"Hanyue Liu, Yanlan Xiao, Chuhao Dai, Keyu Chen, Xinyi Xu, Jianming Cai, Xuguang Hu, Jiaming Guo","doi":"10.1111/cpr.70056","DOIUrl":"https://doi.org/10.1111/cpr.70056","url":null,"abstract":"<p><p>Autophagy is an evolutionarily conserved process of cell self-catabolism that provides a minimum level of energy for cellular homeostasis during metabolic stress. In radiotherapy (RT), it has been explicitly explained that autophagy plays a dual role in tumour control by tuning cellular radiosensitivity. However, the underlying molecular mechanism remains a conundrum. Therefore, it is of utmost importance to gain insight into the molecular mechanisms elaborating the autophagy-mediated radiosensitivity and craft refined RT strategies for different tumours. Distinguishing it from previous reviews in the field, here we discuss the mechanisms of autophagy, especially its pro-survival and growth-suppressing mechanisms via regulation of radiosensitivity. We further outline some frontier RT adjuvant therapies targeting autophagy, in an endeavour to shed some light on the autophagy-mediated pathways to harness radiosensitivity.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70056"},"PeriodicalIF":5.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to \"Memory Inflation: Beyond the Acute Phase of Viral Infection\".","authors":"","doi":"10.1111/cpr.70054","DOIUrl":"https://doi.org/10.1111/cpr.70054","url":null,"abstract":"","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70054"},"PeriodicalIF":5.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dual Role of Natural Killer Cells in Early Pregnancy: Immunopathological Implications and Therapeutic Potential in Recurrent Spontaneous Abortion and Recurrent Implantation Failure.","authors":"Defeng Guan, Zhou Chen, Yuhua Zhang, Wenjie Sun, Lifei Li, Xia Huang","doi":"10.1111/cpr.70037","DOIUrl":"https://doi.org/10.1111/cpr.70037","url":null,"abstract":"<p><p>Natural killer (NK) cells are critical regulators of immune processes during early pregnancy, playing a key role in maintaining maternal-foetal immune tolerance and supporting successful implantation. In particular, uterine NK cells, a specialised subset of NK cells, facilitate trophoblast invasion, spiral artery remodelling and placental establishment. Dysregulation of NK cell activity, however, has been implicated in pregnancy complications, notably recurrent spontaneous abortion (RSA) and recurrent implantation failure (RIF). Aberrant NK cell functions, such as heightened cytotoxicity or defective immune signalling, can disrupt the balance between immune tolerance and response, leading to impaired placental development, reduced trophoblast activity and compromised uteroplacental blood flow. This review examines the role of NK cells in early pregnancy, emphasising their contributions to immune modulation and placentation. It also investigates the mechanisms by which NK cell dysfunction contributes to RSA and RIF, and explores therapeutic strategies aimed at restoring NK cell balance to improve pregnancy outcomes. A deeper understanding of NK cell interactions during early pregnancy may provide critical insights into the pathogenesis of pregnancy failure and facilitate targeted immunotherapeutic approaches.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70037"},"PeriodicalIF":5.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tianlun Zhao, Jiawei Di, Yu Kang, Haojie Zhang, Senyu Yao, Bin Liu, Limin Rong
{"title":"TREM2 Impedes Recovery After Spinal Cord Injury by Regulating Microglial Lysosomal Membrane Permeabilization-Mediated Autophagy.","authors":"Tianlun Zhao, Jiawei Di, Yu Kang, Haojie Zhang, Senyu Yao, Bin Liu, Limin Rong","doi":"10.1111/cpr.70047","DOIUrl":"https://doi.org/10.1111/cpr.70047","url":null,"abstract":"<p><p>Microglia, considered as the main immune responder, play an important role in regulating neuroinflammation in central nervous system (CNS) disorders. Our previous work found that TREM2 is highly expressed in microglia and is related to their functional state. However, the specific role of TREM2 in spinal cord injury has not yet been explored. To further investigate the potential mechanism of TREM2, we performed single-cell sequencing on wild-type (Wt) and Trem2<sup>-/-</sup> mice before and after spinal cord injury. Compared to Wt mice, the lysosome, autophagy and membrane-related pathways are more strongly activated in Trem2<sup>-/-</sup> mice, suggesting that TREM2 may exert its effects by influencing lysosomal membranes and autophagy. Mechanistically, we demonstrated that the knockout of Trem2 can reduce the nuclear translocation of TFEB by decreasing the phosphorylation of Syk. Furthermore, we validated that in vitro and in vivo silencing Trem2 can promote autophagy by repairing lysosomal membrane permeabilization. Through immunofluorescence, 3D gait analysis, motor evoked potential experiments, H&E staining and Masson staining, we demonstrated that the increased level of autophagy can rescue more microglia in vivo and promote both functional and histological recovery of spinal cord injury. Collectively, these results not only suggest that microglial lysosomal autophagy is regulated in a TREM2-dependent LMP manner, but also, more importantly, they provide a promising clinical translation strategy based on gene therapy for lysosome-related central nervous system disorders.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70047"},"PeriodicalIF":5.9,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}