Current gene therapy最新文献

{"title":"siRNA and mRNA Therapeutics: A Comprehensive Review of Mechanisms, Delivery Strategies, Clinical Applications, and Future Directions in Precision Pharmacology.","authors":"Ritu Dahiya, Ajay Pal Singh, Pooja Mathur, Laxmi Rani, Ebrahim Ahmed Jaber Al Hatef, Hadeel Khalid Alharbi, Parakh Basist, Sradhanjali Mohapatra, Kanika Goyal","doi":"10.2174/0115665232434772251211065217","DOIUrl":"https://doi.org/10.2174/0115665232434772251211065217","url":null,"abstract":"<p><p>Small interfering RNA (siRNA) and messenger RNA (mRNA) therapeutics represent transformative approaches in precision pharmacology, enabling targeted gene silencing and protein expression, respectively. This review provides a comprehensive analysis of their molecular mechanisms, delivery strategies, clinical applications, and future directions. By leveraging RNA interference for siRNA and translational machinery for mRNA, these therapeutics address previously untreatable diseases, including genetic disorders, cancers, and infectious diseases. Advances in nanoparticle- based delivery systems, such as lipid nanoparticles, have overcome historical barriers like RNA instability and immune activation. Current clinical applications, including FDA-approved therapies, highlight their efficacy, while ongoing challenges, such as off-target effects and scalable production, are discussed. Future directions emphasize personalized medicine, combination therapies, and novel delivery platforms to enhance therapeutic precision and accessibility.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966872","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":"Advances in the Application of Adenine Base Editor (ABE) in Biology and Medicine: Prospects and Challenges.","authors":"Ziyang Yue, Haonan Li, Yi Hu, Decheng Wang, Xuan Xia","doi":"10.2174/0115665232488406260825103338","DOIUrl":"https://doi.org/10.2174/0115665232488406260825103338","url":null,"abstract":"<p><p>Adenine base editors (ABEs), which achieve A·T to G·C conversions in the genome precisely, symbolize a groundbreaking development in genetic engineering across animal, plant, and microbial systems. This review systematically summed up the research progress and current challenges of ABE in medical and biological applications: it outlined the historical context and pivotal milestones of its technological development; it emphasized major therapeutic advances for genetic diseases including spinal muscular atrophy, mitochondrial genetic disorders, and hyperlipidemia; it provided a comprehensive overview of its prospective uses for enhancing genetic traits in agricultural crops, including grains and fruits; this review conducted a multidimensional assessment of ABE performance through systematic comparison with other base editing technologies, comprehensively evaluating both editing efficiency and inherent limitations. It specifically addresses biosecurity risks such as off-target effects and genomic instability. Finally, safety concerns were proposed as the central challenge hindering its clinical translation, although ABE holds immense promise for precision medicine and agricultural breeding. Unlike previous reviews that mainly summarized early ABE development and general applications, this review particularly emphasizes recently engineered ABE systems, translational bottlenecks, delivery strategies, comparative clinical feasibility, and unresolved biosafety challenges that currently limit broader therapeutic and agricultural applications.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966820","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":"Efficacy and Safety of Immune Checkpoint Inhibitors for Recurrent or Metastatic Cervical Cancer: A Systematic Review and Meta-Analysis.","authors":"Yuanyuan Li, Songyi Wang, Yirui Mai, Zhixi You, Yu Wang, Jiake Wang, Ye Lei","doi":"10.2174/0115665232459323260803060556","DOIUrl":"https://doi.org/10.2174/0115665232459323260803060556","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer is a major global health challenge and requires the exploration of novel treatment strategies. Immune checkpoint inhibitors, particularly those targeting Programmed Death 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), have emerged as promising therapeutic agents in oncology. This study aimed to evaluate the efficacy and safety of these inhibitors in the treatment of cervical cancer.</p><p><strong>Methods: </strong>A comprehensive literature search was conducted across PubMed, Embase, Web of Science, Scopus, the Cochrane Library, and the China National Knowledge Infrastructure to identify studies published up to November 1, 2024. A total of 26 relevant studies were included, including 21 Non-Randomized Controlled Trials (Non-RCTs) and 5 Randomized Controlled Trials (RCTs). The analysis primarily evaluated the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced cervical cancer. The primary outcomes included the objective response rate, disease control rate, progression-free survival, overall survival, and adverse events. Non-RCTs and RCTs were evaluated using ROBINS-I and ROB 2, respectively. Data analysis and visualization were performed using STATA 17.0 and GraphPad. This study has been registered with PROSPERO (registration number CRD42024510357).</p><p><strong>Results: </strong>Therapeutic outcomes indicated that the objective response rate in patients with cervical cancer was 44.30% (95% CI 31.06%-57.93%), and the disease control rate was 63.05% (95% CI 51.67%-73.78%). The complete response, partial response, stable disease, and progressive disease rates were 12.58% (95% CI 6.46%-20.13%), 26.87% (95% CI 19.92%-34.40%), 17.95% (95% CI 12.50%-24.07%), and 27.61% (95% CI 17.68%-38.71%), respectively. The median PFS was 6.22 months (95% CI 3.86-8.59), with 6- and 12-month PFS rates of 58.93% (95% CI 47.78%-69.65%) and 45.20% (95% CI 32.73%-57.96%), respectively. The median OS was 14.81 months (95% CI 8.45-21.16), with 6- and 12-month OS rates of 86.57% (95% CI 80.92%-91.42%) and 70.34% (95% CI 61.47%-78.53%), respectively. Regarding safety, the incidence of treatment-related adverse events was 83.24% (95% CI 73.93%-90.94%), serious adverse events was 25.71% (95% CI 15.33%-37.58%), adverse drug reactions was 71.57% (95% CI 57.61%-83.78%), and immunerelated adverse events was 34.26% (95% CI 27.11%-41.76%). Common treatment-related adverse events included anemia, diarrhea, nausea, and leukopenia.</p><p><strong>Conclusion: </strong>The findings indicate that immune checkpoint inhibitors represent a potentially effective treatment option for patients with cervical cancer; however, their safety profile warrants careful consideration. Combination therapies involving PD-1 inhibitors appear to improve efficacy while maintaining manageable safety.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886533","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":"Targeting FUNDC1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Suppressing Mitochondrial Function.","authors":"Weinan Yao, Dong Guo, Xueyuan Zhang, Xingyu Du, Wenbin Shen, Shuchai Zhu","doi":"10.2174/0115665232502208260729114754","DOIUrl":"https://doi.org/10.2174/0115665232502208260729114754","url":null,"abstract":"<p><strong>Introduction: </strong>As one of the most important treatments of Esophageal Squamous Cell Carcinoma (ESCC), the therapeutic effect of radiotherapy is still limited. FUN14 DomainContaining 1 (FUNDC1), a key regulator of mitophagy, has been implicated in tumor progression in several malignancies. However, its role in ESCC remains unclear. This study investigated the role of FUNDC1 in mitochondrial morphology, mitophagy, and radiosensitivity in ESCC cells.</p><p><strong>Materials and methods: </strong>We evaluated FUNDC1 expression in ESCC using bioinformatics and immunohistochemistry. The effects of FUNDC1 knockdown on malignant behavior were assessed through CCK-8, wound healing, and transwell assays. Flow cytometry analyzed cell cycle and apoptosis. Radiosensitivity was determined by colony formation assays with survival curve fitting using the Linear-Quadratic (LQ) model. DNA damage was assessed by γH2AX foci formation. Mitochondrial morphology and mitophagy were examined using live cell staining and immunofluorescence. Western blotting measured protein expression.</p><p><strong>Results: </strong>FUNDC1 expression was elevated in multiple cancers. High FUNDC1 expression was associated with advanced tumor stage and showed an unfavorable survival trend in ESCC patients. In our clinical cohort, a significant association with overall survival was observed in the M0 subgroup. FUNDC1 knockdown inhibited proliferation, migration, and invasion, particularly after irradiation. It also enhanced IR-induced G2/M arrest, γH2AX foci formation, and apoptosis. Mechanistically, FUNDC1 knockdown attenuated IR-induced mitochondrial fission and mitophagy-related changes, accompanied by increased cytochrome c release and apoptosis. In addition, FUNDC1 knockdown was associated with reduced total HMGB1 expression, impaired HMGB1 nuclear-to-cytoplasmic translocation, and suppressed RAGE/ERK activation, and these changes were partially reversed by 14-3-3σ overexpression.</p><p><strong>Discussion: </strong>Our findings suggest that FUNDC1 promotes malignant behavior and radioresistance in ESCC cells. FUNDC1 knockdown was accompanied by reduced mitochondrial fission, attenuated mitophagy-related changes, and enhanced apoptosis after irradiation. FUNDC1 may also modulate HMGB1/RAGE/ERK signaling through a mechanism involving 14-3-3σ, although the precise causal relationships remain to be established.</p><p><strong>Conclusion: </strong>FUNDC1 knockdown inhibited malignant behavior and enhanced radiosensitivity in ESCC cells, associated with altered mitochondrial morphology, reduced mitophagy-related changes, and suppression of HMGB1/RAGE/ERK signaling. FUNDC1 may serve as a potential target for radiosensitization in ESCC.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808380","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":"The TRH-TRHR Axis Acts as a Metabolic Checkpoint for Ammonia Tolerance in AML: Therapeutic Targeting via Imiquimod and Itraconazole.","authors":"Yan Wang, Xinhui Qiu, Weiwei Liu, Zhixiang Lei, Zheying Wang, Xiaoyu Zhang, Hongxing Wang, Hongchun Wang","doi":"10.2174/0115665232513251260729055334","DOIUrl":"https://doi.org/10.2174/0115665232513251260729055334","url":null,"abstract":"<p><strong>Introduction: </strong>Metabolic reprogramming facilitates survival in Acute Myeloid Leukemia (AML), but the molecular checkpoints governing ammonia tolerance remain unclear. This study aimed to investigate the role of the TRH/TRHR axis in AML ammonia tolerance and identify potential therapeutic interventions.</p><p><strong>Methods: </strong>Ammonia Metabolism-Related Genes (AMRGs) were initially identified, and core prognostic genes were screened using 101 combinations of 10 machine learning algorithms. The optimal drug combination was derived by using the Biological Factor-Regulated Neural Network (BFReg- NN) model, followed by molecular docking. A risk signature was constructed and evaluated using survival analysis, time-dependent Receiver Operating Characteristic (ROC) curves, calibration curves, Decision Curve Analysis (DCA), and Cox regression. By systematically assessing ammonia levels, cell proliferation, apoptosis, and ROS accumulation, alongside functional rescue and genetic validation experiments, we elucidated the underlying mechanisms of ammonia tolerance in AML and validated the therapeutic efficacy of the screened drugs.</p><p><strong>Results: </strong>A total of 6 core prognostic genes (TRH, TCIRG1, CXCL10, RUFY4, GPR12, CCR5) were screened out through machine learning. The BFReg-NN model predicted imiquimod and itraconazole as the optimal drug combination. The constructed risk model demonstrated moderate prognostic predictive ability. An abnormal \"high ammonia and low TRH\" state in AML was identified. Exogenous TRH treatment significantly reversed ammonia tolerance, suppressed AML cell proliferation, increased ROS accumulation, and promoted AML cell death. Combination treatment with imiquimod and itraconazole significantly inhibited AML cell proliferation and promoted apoptosis, with TRH/TRHR signaling playing an important role. Additional validation in THP-1 cells and TRHR knockdown experiments further supported the involvement of TRH/TRHR signaling.</p><p><strong>Discussion: </strong>Collectively, AML cells demonstrate a state of high ammonia tolerance. Our findings suggest that the TRH-TRHR axis may serve as an ammonia metabolism-related checkpoint in AML and indicate that the imiquimod-itraconazole regimen represents a potential therapeutic strategy for targeting ammonia tolerance in AML.</p><p><strong>Conclusion: </strong>AML cells exhibit a state of high ammonia tolerance associated with reduced TRH expression. Our study suggested that TRH/TRHR signaling is involved in regulating ammonia tolerance in AML.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808321","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":"ZBTB33/RBM15 Axis Upregulates MACC1 to Promote the Malignant Progression of Colorectal Cancer.","authors":"Lichun Wang, Bin Guo, Xueping Jiao, Quanmao Zhang, Sheng Gao","doi":"10.2174/0115665232510920260717033443","DOIUrl":"https://doi.org/10.2174/0115665232510920260717033443","url":null,"abstract":"<p><strong>Background: </strong>Extensive clinical evidence has identified metastasis-associated colon cancer 1 (MACC1) as a pivotal cancer-promoting gene that actively fuels the advancement of neoplasms. However, the upstream transcriptional regulators of MACC1 and the specific posttranscriptional mechanisms involving N6-methyladenosine (m6A) modification that govern its expression remain largely undefined. This study aims to elucidate the regulatory network controlling MACC1 expression and its impact on colorectal cancer (CRC) progression.</p><p><strong>Methods: </strong>MACC1 expression and its potential regulators were systematically analyzed using public databases, including GEPIA, TCGA, and TIMER2, alongside clinical tissue samples and cell lines (SW480, HCT-116, and SW620). Functional experiments were conducted to assess cell viability, proliferation, invasion, and ferroptosis. These methodological approaches encompassed chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), as well as dual-luciferase reporter systems. Furthermore, in vivo validation was performed using a nude mouse xenograft model.</p><p><strong>Results: </strong>MACC1 was significantly upregulated in CRC tissues and cell lines, and its high expression correlated with an unfavorable prognosis. Functional assays revealed that silencing MACC1 inhibited CRC cell proliferation and invasion while inducing ferroptosis. Mechanistically, RNA binding protein 15 (RBM15) was identified as a key m6A methyltransferase component that stabilized MACC1 mRNA in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)- dependent manner. Furthermore, zinc finger and BTB domain-containing 33 (ZBTB33) was found to transcriptionally activate RBM15 by binding to its promoter region. Knockdown of RBM15 inhibited CRC cell invasion and proliferation and induced ferroptosis; these effects were notably reversed by MACC1 overexpression. Moreover, ZBTB33 silencing inhibited the key malignant phenotypes of CRC cells and induced ferroptosis by regulating RBM15. Further, RBM15 depletion suppressed tumor growth, which was attenuated by the restoration of MACC1.</p><p><strong>Discussion: </strong>Our study unveils a novel ZBTB33/RBM15/MACC1 signaling axis that drives CRC progression. Clinically, these findings not only deepen the understanding of m6A-mediated posttranscriptional regulation in CRC but also identify this axis as a promising therapeutic target for overcoming ferroptosis resistance and improving patient outcomes.</p><p><strong>Conclusion: </strong>These findings uncover a novel ZBTB33/RBM15/MACC1 regulatory axis in CRC, where ZBTB33 transcriptionally activates RBM15 to enhance MACC1 mRNA stability, ultimately suppressing ferroptosis and promoting tumor progression.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808349","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":"Integration of Single-Cell Transcriptomics and Network-Based Machine Learning Identifies Bone Marrow Mesenchymal Stem Cell-Associated Candidate Biomarkers and Exploratory Immune Correlates in Osteoarthritis.","authors":"Hanyu Wang, Zhikang Chen, Shikai Chen, Honglin Pi, Qianqian Liang, Li Wang","doi":"10.2174/0115665232502221260728112834","DOIUrl":"https://doi.org/10.2174/0115665232502221260728112834","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Osteoarthritis (OA) is a whole-joint disease involving coordinated changes in subchondral bone, Bone Marrow Mesenchymal Stem cells (BM-MSCs), and synovium. This study aimed to identify BM-MSC-associated and OA-related candidate biomarkers and evaluate their potential diagnostic and immune-related relevance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The scRNA-seq dataset GSE147287 was used to construct an OA subchondral bonemarrow atlas, identify BM-MSC populations, perform BM-MSC sub-clustering, and derive BMMSC co-expression modules and hub genes using hdWGCNA. Three synovial transcriptomic datasets (GSE55457, GSE55235, and GSE55584) were integrated as the training cohort after datasetspecific log2 (expression + 1) transformation and ComBat correction, whereas GSE12021 was processed independently as an external validation cohort. BM-MSC hub genes were intersected with OA-related synovial DEGs and further prioritized using LASSO, SVM-RFE, and XGBoost. A combined four-gene model was constructed using Firth's penalized logistic regression. Diagnostic performance was evaluated by ROC analysis, cellular expression was validated in IL-1β-stimulated hBMSCs by qRT-PCR, and immune-cell and Hallmark pathway correlations were assessed using ssGSEA and Spearman analysis with Benjamini-Hochberg correction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The single-cell atlas contained nine major cell types, and BM-MSC sub-clustering identified four transcriptionally distinct subclusters. Cross-tissue integration yielded 35 BM-MSCassociated and OA-related candidate genes, from which EFEMP2, CTSO, SPRY1, and NFIC were selected. In the training cohort, the AUCs were 0.890 (95% CI, 0.792-0.989) for EFEMP2, 0.896 (95% CI, 0.802-0.990) for CTSO, 0.892 (95% CI, 0.797-0.987) for SPRY1, and 0.769 (95% CI, 0.630-0.908) for NFIC. In GSE12021, the corresponding AUCs were 0.867 (95% CI, 0.698-1.000), 0.922 (95% CI, 0.801-1.000), 0.922 (95% CI, 0.797-1.000), and 0.856 (95% CI, 0.674-1.000), respectively. The combined four-gene model achieved AUCs of 0.998 (0.993-1.000) in the training cohort and 1.000 (1.000-1.000) in GSE12021. qRT-PCR confirmed the upregulation of EFEMP2 and CTSO and the downregulation of SPRY1 and NFIC in IL-1β-stimulated hBMSCs. After Benjamini- Hochberg correction, no immune-cell or Hallmark pathway correlations remained statistically significant, although several moderate exploratory trends were observed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;EFEMP2, CTSO, SPRY1, and NFIC represent BM-MSC-associated and OA-related candidate biomarkers. These findings provide a hypothesis-generating framework for characterizing OA-related stromal states and developing future tissue-fitness or patient-stratification tools, but further clinical and tissue-specific validation is required.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;EFEMP2, CTSO, SPRY1, and NFIC were identified as BM-MSC-associated and OArelated candidate biomarkers. These findings provide a hypothesis-genera","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808347","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":"Innovative Insights into Osteosarcoma: Unraveling the Role of LncRNAs, miRNAs, and CircRNAs in Tumorigenesis and Therapeutic Resistance.","authors":"Ali Yeganeh, Masoud Ghorbanlo, Siamak Kazemi, Tohid Emami Meybodi, Khatere Mokhtari, Pejman Molaei, Shayan Amiri, Hamid Tanzadehpanah","doi":"10.2174/0115665232405081251111185550","DOIUrl":"https://doi.org/10.2174/0115665232405081251111185550","url":null,"abstract":"<p><p>Osteosarcoma (OS) is the most common form of primary bone malignancy, characterized by the production of osteoid tissue and contributing significantly to cancer-related mortality in both pediatric and adult populations. The etiology of OS remains multifactorial, involving genetic predispositions, environmental exposures, and complex molecular alterations. Despite advances in surgery and chemotherapy, therapeutic outcomes remain suboptimal due to the high propensity for metastasis and chemoresistance. This review explores recent insights into the genomic landscape of OS, with a focus on the regulatory roles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in tumor initiation, progression, and therapy resistance. We further examine emerging strategies that target these non-coding RNAs as potential therapeutic agents or biomarkers for diagnosis and prognosis. Ultimately, this review emphasizes the need for innovative RNA-based approaches to improve the clinical management and survival outcomes of osteosarcoma patients.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808417","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":"Blocking the Phase Separation of hnRNP L Attenuates Pulmonary Fibrogenesis by Inhibiting Fibroblast-to-myofibroblast Differentiation.","authors":"Mingze Wang, Huiling Yang, Yujie Wang, Yaqin Zhao, Di Kang, Xiaodong Song, Changjun Lv, Jinjin Zhang","doi":"10.2174/0115665232425283251206012409","DOIUrl":"https://doi.org/10.2174/0115665232425283251206012409","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Pulmonary fibrosis is an interstitial lung disease characterized by diverse etiologies and unknown mechanisms. Phase separation has been implicated in the development of numerous diseases, but its role in the pathogenesis of pulmonary fibrogenesis remains unclear. In this study, we explored whether heterogeneous nuclear ribonucleoprotein L (hnRNP L) can form phase-separation condensates that contribute to the progression of pulmonary fibrosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Pulmonary fibrosis was modeled in vitro using TGF-β1-treated fibroblasts and in vivo by intratracheal bleomycin administration in mice. Phase-separation formation was evaluated by droplet formation and fluorescence recovery after photobleaching experiments. Adeno-associated virus vectors overexpressing full-length hnRNP L or hnRNP L-Δ26-111 & 274-374 (truncation of amino acid fragments 26-111 and 274-374) were constructed and delivered into murine lungs using a Penn-Century MicroSprayer device. Micro-computed tomography imaging, forced vital capacity tests, hematoxylin and eosin staining, and Masson's trichrome staining were performed to assess the anti-fibrotic effect of disrupting hnRNP L phase separation. RNA-seq was employed to explore the underlying molecular targets of hnRNP L.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In vivo and in vitro results revealed that the role of hnRNP L in promoting fibroblast differentiation depended on its phase separation, and the amino acid fragments 26-111 and 274-374 were essential to this process. Phenotypic, physiological, and histological analyses demonstrated that hnRNP L overexpression accelerated the development of pulmonary fibrogenesis. In contrast, truncated hnRNP L-Δ26-111 and 274-374 improved lung tissue structure and function and reduced collagen deposition by blocking hnRNP L phase separation. RNA-seq results showed that a total of 1,155 dysregulated genes (FDR &lt; 0.05, |logFC| &gt; 1) were detected after silencing hnRNP L using small interfering RNA (siRNA) in TGF-β1-treated MRC-5 cells. Most differentially expressed genes were related to lung fibrosis, including TGFBR1, CXCL8, WWTR1, FAP, VIM, α-SMA, and collagen. The RNA levels of these genes were evidently regulated by silencing or overexpressing hnRNP L. Notably, we observed that hnRNP L phase separation promoted histone modifications such as H3K27ac, H4K8la, H4K12la, and H4K16la, which are associated with active chromatin.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Our findings reveal that TGF-β1-enhanced phase separation of the chromatin-associated RBP hnRNP L promotes gene transcription and facilitates profibrotic phenotypes in lung myofibroblasts, suggesting a phase-separation-based therapeutic strategy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Blocking hnRNP L phase separation inhibited fibroblast-to-myofibroblast differentiation, attenuating pulmonary fibrogenesis. This study reveals a novel regulatory mechanism by which phase separation contributes to the ","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789485","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":"Targeting PD-1/PD-L1 and CTLA-4 Immune Checkpoints for Therapeutic Advancement in Hepatocellular Carcinoma.","authors":"Krishana Kumar Sharma, Hema Barti, Siddhant Jai Tyagi, Mohd Mohsin, Gajendra Kumar","doi":"10.2174/0115665232419361251203152638","DOIUrl":"https://doi.org/10.2174/0115665232419361251203152638","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with limited effective treatments and a generally poor prognosis. Immune checkpoint pathways, particularly PD-1/PD-L1 and CTLA-4, play a crucial role in modulating the tumor microenvironment (TME) and facilitating immune escape in HCC. PD-1 is expressed on activated T cells, B cells, and macrophages, and interacts with PD-L1, which is often overexpressed on tumor cells and antigen-presenting cells. This interaction leads to T-cell inhibition and tumor immune evasion. Elevated PD-1/PD-L1 expression in HCC correlates with disease progression and poor outcomes. Inhibitors targeting PD-1 or PD-L1 have shown significant clinical benefits in some HCC patients, highlighting the therapeutic potential of this pathway. CTLA-4, another critical checkpoint molecule, negatively regulates immune responses by competing with CD28 for B7 binding on antigen-presenting cells, thereby dampening T-cell activation and proliferation. In HCC, CTLA-4 expression contributes to immune suppression and tumor growth. CTLA-4 blockade combined with PD-1/PD-L1 inhibitors has shown promise in enhancing anti-tumor immunity and improving clinical outcomes in HCC patients. The complex interplay between PD-1/PD-L1 and CTLA-4 pathways in HCC underscores the complexity of immune escape mechanisms. Targeting these checkpoints has the potential to reshape HCC treatment, offering hope for more effective and durable outcomes. Future research should focus on optimizing combination therapies, understanding resistance mechanisms, and identifying biomarkers for better patient stratification and response prediction. Advancements in this field could lead to more personalized and effective treatments, significantly improving the prognosis and quality of life for HCC patients.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788658","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}