Journal of Gene Medicine最新文献

{"title":"Single-Cell RNA Sequencing and Network Pharmacology Reveal the Potential Role of Oxidative Phosphorylation Inactivation in Diagnosing and Treating Chronic Tendon Injuries","authors":"Jie-Jie Niu,&nbsp;Long Wang,&nbsp;Jia-chen Qi,&nbsp;Gui-jun Lu","doi":"10.1002/jgm.70085","DOIUrl":"10.1002/jgm.70085","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic tendon injuries, characterized by persistent pain, reduced flexibility, and impaired function, pose a significant clinical challenge. Current therapeutic strategies for these injuries are limited. This study highlighted the crucial role of OXPHOS in maintaining tendon homeostasis and suggested potential therapeutic strategies targeting the OXPHOS pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>This study utilized both bulk-sequencing (bulk-seq) and single-cell RNA sequencing (scRNA-seq) to analyze the heterogeneity in tenocytes, vascular endothelial cells, tendon-derived stem cells, adipocytes, and neurons from both non-lesional and lesional tendons. Key oxidative phosphorylation (OXPHOS)-related genes, such as COX15, COX4I1, COX5B, COX7A1, COX8A, NDUFA12, NDUFA5, NDUFB10, NDUFB3, NDUFC1, NDUFS1, and NDUFS4, were found to be significantly downregulated in lesional tendons compared with non-lesional ones, indicating impaired energy metabolism. This reduction in OXPHOS activity may contribute to increased necroptosis in chronic tendon injuries. Furthermore, bisphenol A and valproic acid were found to activate OXPHOS-related genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The findings highlighted the crucial role of OXPHOS in maintaining tendon homeostasis and demonstrated potential therapeutic strategies targeting the OXPHOS pathway, such as bisphenol A and valproic acid, to enhance healing in chronic tendon conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The crucial role of OXPHOS in maintaining tendon homeostasis underscores its potential as a therapeutic target, reflecting that strategies aimed at modulating the OXPHOS pathway may provide promising treatment options.</p>\u0000 \u0000 <p>Chronic tendon injuries present a major clinical challenge with limited treatments. This study investigated the molecular mechanisms underlying these injuries using bulk and single-cell RNA sequencing. We identified significant downregulation of oxidative phosphorylation (OXPHOS)-related genes in lesional tendons across multiple cell types, contributing to increased necroptosis. In vitro experiments and molecular docking revealed that valproic acid activates OXPHOS and inhibits necroptosis. These findings highlight the critical role of mitochondrial function in tendon homeostasis and suggest valproic acid as a promising therapeutic candidate for treating chronic tendon injuries by restoring OXPHOS activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 2","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL14 Promotes Ovarian Cancer Progression and Autophagy Through the IKBKE/NF-κB Pathway","authors":"Yan Lingling,&nbsp;Rao Yanqiu,&nbsp;Zhu Xuchao,&nbsp;Liu Menbing,&nbsp;Liu Jiangang","doi":"10.1002/jgm.70084","DOIUrl":"10.1002/jgm.70084","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian cancer remains a leading cause of gynecological malignancy-related deaths, necessitating the identification of novel molecular pathways driving tumor progression. Utilizing a data-driven approach, we conducted bioinformatic analyses of TCGA and GEO datasets, identifying a significant upregulation of CXCL14 in ovarian cancer tissues, which correlates with poor patient survival. Functional assays demonstrated that overexpression of CXCL14 enhances ovarian cancer cell proliferation, invasion, and autophagy. Mechanistically, CXCL14 activates the canonical NF-κB signaling pathway by inducing phosphorylation and degradation of IκBα, leading to phosphorylation and nuclear translocation of p65. Importantly, we identified IKBKE as a critical kinase mediating CXCL14-induced activation of the canonical NF-κB pathway through phosphorylation of IκBα. Knockdown of IKBKE effectively attenuates CXCL14-driven NF-κB activation, thereby suppressing cell proliferation, invasion, and autophagy. In vivo, CXCL14 overexpression markedly enhances ovarian tumor growth, accompanied by increased levels of IKBKE and phosphorylated p65. These findings elucidate a novel regulatory axis, CXCL14/IKBKE/NF-κB, in ovarian cancer progression, highlighting CXCL14 as a potential therapeutic target for ovarian cancer treatment.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146031830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miRNA-Directed Anticancer Strategies: The Emerging Role of Natural Products in Ovarian Cancer","authors":"Rasha Abu-Khudir,&nbsp;Shaza H. Aly,&nbsp;Nehal I. Rizk,&nbsp;Rabab S. Hamad,&nbsp;Heba M. Midan,&nbsp;Mai A. Abd-Elmawla,&nbsp;Sherif S. Abdel Mageed,&nbsp;Ahmed I. Abulsoud,&nbsp;Mohamed Bakr Zaki,&nbsp;Osama A. Mohammed,&nbsp;Ahmed E. Elesawy,&nbsp;Walaa A. El-Dakroury,&nbsp;Ahmed S. Doghish","doi":"10.1002/jgm.70080","DOIUrl":"10.1002/jgm.70080","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian cancer (OC) is still one of the most serious gynecologic malignancies in the world. It is characterized by a significant likelihood of recurrence and resistance to conventional therapies and a lack of efficient screening techniques. MicroRNAs (miRNAs) are small, noncoding RNA molecules that exert pivotal functions in modulating gene expression. miRNAs are improperly regulated in OC, contributing to tumor onset, progression, metastasis, and resistance to chemotherapeutics. As a result, miRNAs are promising therapeutic targets for the treatment of OC. Recently, natural products derived from plants and other sources have drawn more interest because of their potential to modulate miRNA expression. A variety of bioactive substances, such as curcumin, quercetin, and others, have shown the ability to either promote tumor-suppressing miRNAs or suppress tumor-promoting miRNAs. These substances have a great deal of promise for improving the effectiveness of traditional chemotherapy, lowering adverse effects, and providing more individualized treatment plans. Additionally, their capacity to target several miRNAs implicated in cancer-related pathways offers a multimodal strategy for treating OC. We can upgrade the potential therapeutic options for OC and other cancers by exploring novel natural products with miRNA-modulating effects. However, further research is needed to clinically translate miRNA-based therapeutics employing natural compounds, especially in the areas of safety, bioavailability, and drug delivery methods. This review emphasized the implications of miRNAs in OC, the impact of natural products on miRNA regulations, and the potential for incorporating these natural substances into clinical practice for individualized and successful OC treatments.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs as Key Regulators and Potential Biomarkers in Vitiligo Pathogenesis","authors":"Ahmed S. Doghish,&nbsp;Nehal I. Rizk,&nbsp;Osama A. Mohammed,&nbsp;Mohamed Hemdan,&nbsp;Khaled M. Alam-Eldein,&nbsp;Mohamed Salah Basiouny,&nbsp;Khaled Abuelhaded,&nbsp;Hend H. Mohamed,&nbsp;Abanoub A. S. Shaker,&nbsp;Moaz M. Elshafey,&nbsp;Alaa Adel Abo Ella,&nbsp;Reda M. Mansour","doi":"10.1002/jgm.70083","DOIUrl":"https://doi.org/10.1002/jgm.70083","url":null,"abstract":"<div>\u0000 \u0000 <p>Vitiligo involves melanocyte loss, potentially due to oxidative stress, immune dysfunction, and genetics. This article examines microRNAs (miRNAs), noncoding RNAs crucial for gene expression regulation, as they act as molecular switches that can activate or deactivate genes upon translation. It identifies modified miRNA levels in the skin, blood, immune cells, and exosomes of vitiligo patients. These miRNAs are essential for melanocyte viability and for modulating oxidative stress and immunological responses. Specific miRNAs may function as diagnostic or prognostic biomarkers. The review offers an in-depth comprehension of the crucial functions of miRNAs in development.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(−)-Epicatechin Regulates Radioresistance in Lung Adenocarcinoma Through ALKBH5 Downregulation of FOXM1","authors":"Hongying Xu,&nbsp;Jie Xia,&nbsp;Anao Wu,&nbsp;Sihan Zhou,&nbsp;Huahua Zhou,&nbsp;Shixian Wu,&nbsp;Meifang Huang","doi":"10.1002/jgm.70082","DOIUrl":"10.1002/jgm.70082","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung adenocarcinoma (LUAD), a major subtype of non–small-cell lung cancer, exhibits high incidence and mortality rates. Radiotherapy is a critical treatment modality for LUAD, yet its efficacy is often compromised by radiotherapy resistance. (−)-Epicatechin (EC), a natural flavanol derived from <i>Fagopyrum cymosum</i>, has been reported to enhance radiosensitivity in various cancers. However, its specific role and underlying mechanisms in LUAD radiotherapy resistance remain unclear. In this study, we established radiotherapy-resistant cell lines A549R and NCI-H520R by repeatedly irradiating A549 and NCI-H520 cells with gradient doses of X-rays. Furthermore, a xenograft tumor model was constructed by subcutaneously inoculating A549R cells into the left dorsal region of nude mice. The results demonstrated that the forkhead box M1 (FOXM1)—a key oncoprotein implicated in lung cancer proliferation, invasion, and therapy resistance—was significantly upregulated in LUAD tissues and radiotherapy-resistant A549R cells. Knockdown of FOXM1 enhanced radiosensitivity in A549R cells, promoted radiation-induced apoptosis, and suppressed cell proliferation. EC effectively potentiated the radiotherapy response of A549R cells in vitro and attenuated radiotherapy resistance while inhibiting tumor growth in vivo. Mechanistically, EC downregulated ALKBH5, an m6A demethylase known to participate in cancer biology by regulating mRNA demethylation, thereby promoting m6A methylation of FOXM1 mRNA and subsequently suppressing FOXM1 expression, ultimately mitigating radiotherapy resistance in LUAD. This study reveals a novel mechanism by which EC enhances radiosensitivity in LUAD via the ALKBH5/FOXM1 axis, offering a potential therapeutic strategy to overcome radiotherapy resistance in LUAD.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anisomycin Induces Senescence and Death of Ovarian Cancer Stem Cells Through the MicroRNA-340/SENP6/SUMOylation Pathway","authors":"Lian Yang,&nbsp;Ye Xia,&nbsp;Zeyu Cui,&nbsp;Yanchen Lai,&nbsp;Yongyi Huang,&nbsp;Ying Xiong,&nbsp;Juan Chen,&nbsp;Te Liu","doi":"10.1002/jgm.70081","DOIUrl":"10.1002/jgm.70081","url":null,"abstract":"<div>\u0000 \u0000 <p>Ovarian cancer remains a leading cause of gynecologic cancer mortality, in part due to the persistence of ovarian cancer stem cells (OCSCs) that drive tumor recurrence, metastasis, and drug resistance. Anisomycin, a natural antibiotic derived from <i>Streptomyces coelicolor</i>, has previously been shown to exert antitumor effects, but the mechanisms by which it targets OCSCs remain unclear. In this study, primary human OCSCs were isolated and treated with anisomycin to investigate its biological and molecular effects. Cell proliferation, apoptosis, migration, and colony formation were assessed in vitro, and tumorigenicity was evaluated in xenograft mouse models. Transcriptomic, biochemical, and molecular assays were performed to identify downstream pathways. Anisomycin treatment markedly inhibited proliferation and promoted senescence and cell death of OCSCs. Mechanistically, anisomycin induced upregulation of microRNA-340, which in turn suppressed the deSUMOylating enzyme SENP6. This repression increased SUMOylation of key senescence-related proteins, including p53 and p16, leading to stabilization of their expression and enforcement of cell-cycle arrest. Overexpression of microRNA-340 reproduced these effects, both in vitro and in vivo, confirming its central role in mediating anisomycin activity. Bioinformatic analyses further revealed that expression of SENP6 and senescence-associated genes correlated with disease progression and patient survival in ovarian cancer cohorts. These findings identify a previously unrecognized epigenetic mechanism by which anisomycin induces senescence and death in OCSCs, suggesting that targeting the microRNA-340/SENP6/SUMOylation pathway may represent a promising therapeutic approach.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Omics Analysis Reveals the Molecular Subtypes and Confirmed the GREM1 as the Core Gene","authors":"Zhen-Qing Li,&nbsp;Hui-Rong Huang,&nbsp;Ke-Rong Zhai,&nbsp;Bin Li","doi":"10.1002/jgm.70067","DOIUrl":"10.1002/jgm.70067","url":null,"abstract":"<div>\u0000 \u0000 <p>Research on molecular classification of lung cancer based on transcriptomic features has achieved remarkable progress. The complementary information provided by distinct molecular profiles has motivated the integration of multi-omics datasets to refine the classification system for lung cancer. In this study, we employed a computational pipeline incorporating 10 clustering algorithms to integrate multi-omics datasets from lung adenocarcinoma (LUAD) patients, combined with 10 machine learning methods, leading to the identification of high-resolution molecular subtypes and the development of a consensus machine learning–driven signature (CMLS) with robust predictive performance. Our findings reveal that the CS1 subtype is associated with more favorable prognosis and enhanced immune responsiveness. Furthermore, a CMLS model constructed from 26 core genes demonstrated strong prognostic predictive power. Patients with high CMLS scores exhibited lower infiltration of CD8⁺ T cells, poorer survival, and diminished response to immunotherapy. In contrast, the low-CMLS group showed improved clinical outcomes, greater responsiveness to immunotherapy, and a tendency toward an immunologically “hot” tumor phenotype. Integrated multi-omics analysis indicated that Gremlin-1 (GREM1) acts as a key regulator within the differential screening–selected gene aberrant in neuroblastoma (DAN) family genes–mediated transforming growth factor-beta (TGF-β) signaling pathway. In conclusion, our data establish a molecular classifier that stratifies patients into distinct score groups, with those in the low-CMLS group potentially benefiting from treatment with pilaralisib.</p>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"28 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Immune Contexture Model Predicts Prognosis and Immunotherapy Response in Gastric Cancer","authors":"Jiexuan Wang,&nbsp;Xin Yang,&nbsp;Xuan Dai,&nbsp;Zhiqian Hu,&nbsp;Xinxing Li","doi":"10.1002/jgm.70065","DOIUrl":"10.1002/jgm.70065","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gastric cancer (GC) is highly heterogeneous, and current prognostic models fail to fully capture tumor immune characteristics, limiting personalized treatment. This study introduces the Tumor Immune Environment Score (TIES), an immune-based prognostic model designed to enhance risk stratification and predict response to immunotherapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Transcriptomic and clinical data from seven GC cohorts, comprising a total of 1487 patients, were analyzed. The training cohort included GSE15459, GSE62254, GSE84433, and GSE13861, while the validation cohort comprised GSE26899, GSE26901, and TCGA-STAD. Immune-related gene signatures were quantified using ssGSEA and subsequently analyzed via LASSO and Cox regression. Clinical applicability was quantified using decision-curve analysis (DCA) and reclassification metrics (category-free NRI/IDI) for TIES versus TIES + pathological stage. Immunotherapy response was assessed using data from GSE183924, and its associations with immune characteristics, molecular alterations, and drug sensitivity were investigated. For experimental confirmation, we established a 12-gene RT-qPCR panel in 30 institutional GC specimens and computed a weighted qPCR surrogate (qTIES).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A high TIES was associated with worse OS (HR = 2.44, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and DFS (HR = 2.25, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). TIES was an independent prognostic factor and demonstrated superior predictive accuracy compared to TNM staging (AUC = 0.75–0.79 vs. 0.61–0.64, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). Integrating clinical-pathological features with TIES significantly enhanced predictive performance (AUC = 0.75–0.78 vs. 0.61–0.63, &lt;i&gt;p&lt;/i&gt; &lt; 0.01). A low TIES was indicative of an immune-inflamed subtype, characterized by a higher TMB (&lt;i&gt;p&lt;/i&gt; &lt; 0.01) and a greater likelihood of response to immunotherapy (HR = 0.24, &lt;i&gt;p&lt;/i&gt; = 0.014). TIES outperformed TIDE in predicting immunotherapy outcomes, achieving a higher OS C-index (0.780 vs. 0.743) and DFS C-index (0.664 vs. 0.610). At 3 years, TIES + stage yielded a greater net benefit than TIES alone across clinically relevant thresholds (DCA) and improved NRI/IDI.The qPCR panel reproduced axis biology (CSR/TGF-βincreased with NK/Th2 decreased), correlated with pathological stage, stratified OS/DFS by Kaplan–Meier, and showed 3-year discrimination.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;TIES represents a robust immune-based prognostic tool for GC, facilitating improved risk stratification and immuno","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"27 12","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12711383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facilitating Precision Medicine in HCC Patients by Deep Learning–Directed lncRNAs Classification and Ascertaining Causal Markers","authors":"Rashi Jain,&nbsp;Sathish Kumar Mungamuri,&nbsp;Prabha Garg","doi":"10.1002/jgm.70066","DOIUrl":"10.1002/jgm.70066","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a deadly disease, ranking as the fifth most prevalent type of cancer worldwide. To advance precision medicine for HCC, it is imperative to identify novel biomarkers that can facilitate its clinical management. Notably, long noncoding RNAs (lncRNAs) have been demonstrated to play pivotal roles in regulating gene expression and driving tumor progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study harnessed artificial intelligence (AI) to identify novel lncRNA biomarkers using patient data from The Cancer Genome Atlas. A hierarchical composite deep learning (DL) framework was constructed to classify patient samples according to the pathological stages. Explainable AI-based SHapley Additive exPlanations (SHAP) analysis, Kaplan–Meier survival analysis, and biological investigations were performed to identify potential lncRNA biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The DL hierarchical composite framework employed three deep neural networks (DNNs) to classify tumorous liver tissue samples from normal samples (Model 1), distinguish between early and advanced disease stages (Model 2), and further assess the pathological stage of HCC progression (Model 3). Model 1 (AU-ROC = 1.000) and Model 2 (AU-ROC = 0.977) exhibited robust predictive capabilities on unseen data. Model 3 (AU-ROC = 0.774) showed lower performance, highlighting the inherent challenges in the data due to the close association of lncRNAs across advanced HCC stages. SHAP analysis revealed the key lncRNAs driving these classifications, providing insights into the molecular mechanisms of HCC progression. Further investigations identified <i>AC010280.2, AC118754.1, DIO3OS, LINC01748</i>, and <i>LINC00659</i> as potential biomarkers for HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This comprehensive study integrated cutting-edge technologies that pave the way for biomarker discovery, facilitating precision medicine in HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"27 12","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synovial Mesenchymal Stem Cell–Derived Exosomal miR-3614-5p Regulates Macrophage Polarization by Targeting ANXA2 to Relieve Knee Osteoarthritis","authors":"Jianli Xue,&nbsp;Jintao Ye,&nbsp;Pei Han,&nbsp;Yabing Song","doi":"10.1002/jgm.70064","DOIUrl":"https://doi.org/10.1002/jgm.70064","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Synovial mesenchymal stem cell–derived exosomes (SMSC-Exos) can regulate macrophage polarization and alleviate knee osteoarthritis (KOA). However, the underlying mechanisms remain unclear. This study explored the role of miR-3614-5p delivered by SMSC-Exos in KOA progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SMSCs were isolated from rat synovial tissue; SMSC-Exos were collected and identified and co-cultured with lipopolysaccharide (LPS)–stimulated macrophages. Macrophage polarization was assessed by detecting M1- and M2- specific marker proteins using immunofluorescence and Western blot. Interactions between miR-3614-5p and ANXA2 were investigated using dual-luciferase reporter assays and RNA immunoprecipitation. Co-immunoprecipitation was performed to evaluate the interaction between ANXA2 and TLR4. The M1 conditioned medium (M1-CM) was co-cultured with chondrocytes to assess the impact of macrophage polarization on the cellular behaviors of chondrocytes. The KOA rat model was established via anterior cruciate ligament transection and treated with SMSC-Exos injections. Hematoxylin and eosin staining and safranin O-fast green staining were performed to examine cartilage damage and synovial inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In vitro, SMSC-Exos promoted the polarization of LPS-stimulated macrophages from M1 to M2 phenotype, with this effect reversed by reducing miR-3614-5p levels in SMSC-Exos. miR-3614-5p directly targeted and inhibited ANXA2 mRNA expression, preventing activation of the TLR4/MyD88/NF-κB pathway. SMSC-Exos mitigated M1-CM–induced chondrocyte viability loss, apoptosis, and extracellular matrix (ECM) degradation. However, SMSC-Exos with low miR-3614-5p expression failed to show significant protective effects. In vivo, SMSC-Exos alleviated cartilage damage, synovial inflammation, and M1 macrophage infiltration in KOA rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>miR-3614-5p in SMSC-Exos targets ANXA2, promoting macrophage M1-to-M2 polarization, reducing synovial inflammation, and preventing KOA progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"27 12","pages":""},"PeriodicalIF":2.2,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145739921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}