Cancer Cell International最新文献

{"title":"The multiplex crosstalk between non-coding RNAs, programmed cell death and related mechanisms: a dynamic duo in hematological malignancies.","authors":"Mehrdad Hashemi, Niloufar Salimian, Nafiseh Sharifi, Pezhman Shafiei Asheghabadi, Zahra Zarearandi, Fatemeh Abdi, Saranaz SeyedAli Akbar, Reza Mohajer Shirazi, Mehrdad Bagheri Pozve, Armin Nikdehqan, Mehrandokht Nekavand, Zeinab Khazaei Koohpar, Russel J Reiter, Najma Farahani, Mobina Shariatzadeh, Mina Alimohammadi, Payman Rahimzadeh, Afshin Taheriazam, Maliheh Entezari, Kiavash Hushmandi","doi":"10.1186/s12935-025-03999-1","DOIUrl":"10.1186/s12935-025-03999-1","url":null,"abstract":"<p><p>Hematological malignancies, including leukemia, lymphoma, and multiple myeloma (MM), are cancers originating in the hematopoietic system, characterized by diverse pathogenesis and clinical features. Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs, play critical roles in regulating gene expression and influencing cell fate. Accumulating evidence indicates that ncRNAs are key modulators of programmed cell death (PCD) pathways, affecting tumor development, progression, and drug resistance in these malignancies. PCD, a precisely programmed and regulated cell death process, is vital for maintaining tissue homeostasis and preventing the proliferation of dangerous cells. NcRNAs are implicated in the primary mechanisms underlying the development of drug resistance. The evasion of PCD is a hallmark of cancer, and ncRNAs can significantly impact these pathways, with dysregulation observed across leukemia, lymphoma, and myeloma, influencing PCD pathways and clinical outcomes. Understanding the ncRNA-PCD interplay is crucial for developing novel therapeutic strategies and improving patient outcomes. This review explores the functions, regulatory mechanisms, and potential applications of ncRNAs in modulating PCD in hematological malignancies, particularly leukemias, providing insights for future anti-tumor therapies.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"350"},"PeriodicalIF":6.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZNF655 promotes tumor growth and chemoresistance by targeting MAFF-CCND1 axis in ovarian cancer.","authors":"Ying Xiong, Jiaxin Yin, Yulin Huang, Nanbin Luo, Jiali Xia, Chongjie Tong, Min Zheng, Yinglan Liu","doi":"10.1186/s12935-025-03997-3","DOIUrl":"10.1186/s12935-025-03997-3","url":null,"abstract":"<p><p>Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. The role of zinc finger protein 655 (ZNF655) in cancer progression has been highlighted but remains unclear and needs further exploration. In this study, our findings revealed that ZNF655 is aberrantly upregulated in OC. Depletion of ZNF655 inhibited the malignant behaviors of OC, manifested by attenuated proliferation, promoted apoptosis, inhibited migration and reduced stem cell properties. Mechanistically, ZNF655 facilitated nuclear translocation of MAFF transcription factor in OC cells, leading to MAFF's direct binding to the promoter of CCND1 and subsequent transcriptional activation of CCND1. Subsequent rescue experiments demonstrated that CCND1 plays a critical role in mediating ZFN655-dependent proliferation and stemness maintenance. Notably, ZNF655 overexpression conferred paclitaxel resistance in OC cells, suggesting clinical implications for chemoresistance. These in vitro findings were corroborated by murine xenograft models, where ZNF655-overexpressing tumors exhibited accelerated growth kinetics and elevated Ki-67 indices. Importantly, clinical correlation analysis of OC specimens revealed that ZNF655 overexpression correlated with poor patient outcome in OC. In conclusion, these results not only advance the understanding of the molecular mechanisms underlying OC progression but also identify ZNF655 as a potential preclinical therapeutic target for OC treatment.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"351"},"PeriodicalIF":6.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived small extracellular vesicles loaded with functionally active miR-34a mimic can modify the anti-tumor response in 4T1 breast cancer animal model.","authors":"Mahsa Hajivalili, Maryam Hosseini, Bahare Niknam, Kaveh Baghaei, Nariman Mosaffa, Mohsen Rastegari Pouyani, Davar Amani","doi":"10.1186/s12935-025-03994-6","DOIUrl":"10.1186/s12935-025-03994-6","url":null,"abstract":"<p><strong>Background: </strong>A highly detectable problem in Triple-negative breast cancer is reduction of tumor suppressor miRNAs. Thus, this study aimed to use tumor-derived small extracellular vesicles (tsEV) obtained from 4T1 cells as a vehicle for miR-34a-replacement therapy (tsEV-miR-34a-mimic).</p><p><strong>Methods: </strong>We tested 4T1-tsEVs freely, loaded with miR-34a-mimic or miR-34a-inhibitor on 4T1-bearing mice. Frequency of T cells in spleen and Inguinal lymph nodes assessed by flow cytometry then the relative gene expression of target genes of miR-34a evaluated by Real-Time PCR. In addition, level of cytokine secretion considered by ELISA. Additionally, MTT and AnnexinV/PI methods were used to investigate treatments on 4T1 cell proliferation and apoptosis rate, respectively. Afterwards, histopathological evaluation is applied to determine the extent of metastasis. Ultimately, in each group, mice were followed up on to assess the effect of treatments on survival rate.</p><p><strong>Results: </strong>Treatment with tsEV-miR-34a-mimic profoundly increased survival and reduced metastasis in 4T1-bearing mice compared to other groups. Besides, the frequency of CD8 T cells was amplified in tumor tissue and inguinal draining lymph nodes (IDLNs). CD4T cell's polarization toward regulatory T cells (Treg) was reduced. Gene expression pattern of tumor tissue showed a change from immune-suppressive to immune-activating tumor-microenvironment (TME). IL-6 and TGF-β concentrations were significantly reduced. IDLN lymphocytes performed a robust killing ability and actively proliferated in response to 4T1-lysate.</p><p><strong>Conclusion: </strong>Totally, tsEV could be considered as a delivery carrier for miR-34a replacement therapy which also provided an anti-tumor immune response against 4T1- tumor. Thus, this platform could be considered a complementary approach to TNBC therapy.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"352"},"PeriodicalIF":6.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EDC4 enhances multi-drug chemosensitivity in pancreatic cancer via GR50-based profiling.","authors":"Cheng Qin, Tianyu Li, Bangbo Zhao, Zeru Li, Yutong Zhao, Xiangyu Zhang, Yiping Xie, Yutong Yan, Jiashu Han, Qianqian Shao, Chen Lin, Weibin Wang","doi":"10.1186/s12935-025-04000-9","DOIUrl":"10.1186/s12935-025-04000-9","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with drug resistance significantly impeding effective chemotherapy. The clinical importance of key genes in PDAC chemoresistance remains unclear.</p><p><strong>Methods: </strong>Cytotoxicity assays were conducted on eight PDAC cell lines treated with gemcitabine, albumin paclitaxel, irinotecan, 5-FU, and cis-platinum. Based on GR50 values, cell lines were categorized as chemosensitive (CS) or chemoresistant (CR). RNA-seq data from the Cancer Cell Line Encyclopedia were analyzed for differential gene expression. Various statistical methods, including univariate Cox, LASSO, random forest, and multivariate Cox regression, were employed to construct a risk signature. This model's effectiveness was validated using time-dependent ROC curves and Kaplan-Meier survival analysis in TCGA and GSE57495 + GSE28735 combined datasets. Downstream molecules of core genes were explored, and the core gene's function was validated through in vivo and in vitro experiments.</p><p><strong>Results: </strong>Drug resistance profiles were established based on GR50 values. EDC4 and USP20 were identified as key genes in the risk signature. qRT-PCR validated core gene expressions in PDAC cell lines. EDC4 was selected for further analysis due to its highest correlation coefficient in the multivariate Cox regression model. EDC4 knockdown increased proliferation and chemoresistance in MIA PaCa-2 cells, while overexpression inhibited these traits in AsPC-1 cells. MATN3 and SGCE were identified as downstream targets of EDC4. Immunohistochemistry of tissue microarrays confirmed that low EDC4 levels were associated with poor prognosis in PDAC, highlighting its potential as a therapeutic target.</p><p><strong>Conclusion: </strong>PDAC cell lines exhibit distinct chemoresistance capabilities. EDC4 and its downstream targets MATN3 and SGCE play significant roles in PDAC multidrug chemoresistance, providing novel insights for treatment.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"347"},"PeriodicalIF":6.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Centromere protein I facilitates breast cancer tumorigenesis and disease progression through modulation of Wnt/β-Catenin signaling.","authors":"Chaoshen Wu, Yibing Zhou, Yuxiao Mu, Yijie Cheng, Wenqian Xu, Mengna Huang, Jingyuan Xu, Ming Li, Jianfeng Gu, Xuli Meng, Da Qian","doi":"10.1186/s12935-025-04001-8","DOIUrl":"10.1186/s12935-025-04001-8","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BCa) is a major contributor to female mortality worldwide. Treatment resistance and tumor heterogeneity contribute to the lack of effective therapeutic targets, posing a significant challenge in BCa management. CENPI, a core centromere protein involved in chromosome segregation, has emerging evidence implicating it in oncogenesis across diverse malignancies. However, its functional and molecular mechanisms in BCa remain unclear.</p><p><strong>Methods: </strong>We analyzed CENPI expression and its clinical significance by using the BCa dataset from the Cancer Genome Atlas (TCGA) and immunohistochemical staining of 3 human BCa tissue samples. Cellular functional assays and mice xenograft models were utilized to assess the effects of CENPI on BCa growth. RNA sequencing combined with bioinformatics analysis was conducted to elucidate the molecular mechanisms underlying CENPI function, with further validation through Western blotting, immunofluorescence, and TOP/FOP flash assays.</p><p><strong>Results: </strong>CENPI was aberrantly overexpressed in BCa, with elevated expression levels strongly associated with disease progression and poor prognosis. Functional assays demonstrated that CENPI significantly promoted breast carcinogenesis in both cellular and animal models. Mechanistically, CENPI increased BCa progression and malignant phenotypes by modulating the Wnt/β-catenin axis.</p><p><strong>Conclusions: </strong>CENPI is a critical oncogene in BCa, driving tumorigenesis and disease progression via the Wnt/β-catenin axis, which represents a promising biomarker and therapeutic target for BCa.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"348"},"PeriodicalIF":6.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning on transcription factor expression profiles for precision breast cancer therapy.","authors":"Xiaonan Zhang, Simin Min, Ning Zhang, Xiaoyu Shi, Zhaogen Cai, Di Yang, Zixin Meng, Yunxia Zhao, Ni Ni, Tao Wang","doi":"10.1186/s12935-025-03987-5","DOIUrl":"10.1186/s12935-025-03987-5","url":null,"abstract":"<p><strong>Background: </strong>Although breast cancer is a significant heterogeneous disease with an increasing global prevalence, precise prognostic evaluation is a vital aspect of designing personalized therapy strategies and upholding patients' survival rates. With the incorporation of artificial intelligence technology, in particular, machine learning, cancer prognosis and prediction have significantly been redefined.</p><p><strong>Methods: </strong>In this study, we adopted a ten-fold cross-validation method to construct a Machine Learning-Derived Transcription Factor Signature (MDTS) across 108 algorithmic combinations. The optimal model was selected based on the highest average C-index across ten cohorts. We integrated single-cell data with multi-omics analysis to comprehensively assess the robustness of the MDTS model at both molecular and genomic levels. The MDTS demonstrated superior predictive power, outperforming 103 existing signatures and accurately predicting breast cancer outcomes across 10 independent cohorts.</p><p><strong>Results: </strong>Our findings revealed that patients with low MDTS scores are more likely to benefit from immunotherapy, while the PAC-1 drug was identified as the most targeted agents to the chemotherapy with high MDTS score.</p><p><strong>Conclusions: </strong>These insights will open the door to delivering cutting-edge MDTS strategies to customizing breast cancer therapies.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"346"},"PeriodicalIF":6.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of GPD2 and glycolysis-related genes in cholangiocarcinoma: insights into prognostic biomarkers and tumor-immune interactions.","authors":"Yongqing Zhao, Weixiong Zhu, Bo Ren, Wenke Qin, Wence Zhou","doi":"10.1186/s12935-025-03965-x","DOIUrl":"10.1186/s12935-025-03965-x","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) remains a challenging malignancy with limited therapeutic options and poor prognosis. This study investigates the role of glycerol-3-phosphate dehydrogenase 2 (GPD2) and associated glycolysis-related genes in cancer, with a focus on CCA.</p><p><strong>Methods: </strong>We employed a comprehensive multi-omics approach, including genomic, transcriptomic, and single-cell analyses, to explore GPD2's function across various cancers. In vitro experiments validated GPD2's role in CCA. A glycolysis-related prognostic signature was developed and analyzed for its clinical and biological implications.</p><p><strong>Results: </strong>GPD2 was overexpressed in most cancers and correlated with adverse outcomes, genomic instability, and altered immune infiltration. In CCA, GPD2 knockdown suppressed cell proliferation, migration, and glycolytic activity. A four-gene glycolysis-related signature (PTBP3, REEP3, GPRC5A, HN1) successfully classified CCA patients into low and high-risk categories, demonstrating strong prognostic value. The high-risk group displayed distinct immune infiltration patterns, characterized by a decrease in CD8 + T cells and an elevation in M0 macrophages and neutrophils. Single-cell analysis showed that the signature genes were primarily expressed in malignant epithelial cells and provided clues into potential mechanisms of tumor-immune interactions.</p><p><strong>Conclusion: </strong>This study highlights the potential of GPD2 and the glycolysis-related gene signature as prognostic biomarkers and therapeutic targets in CCA. The signature offers insights into tumor biology, immune interactions, and potential personalized treatment strategies, paving the way for improved management of this aggressive cancer.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"345"},"PeriodicalIF":6.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of ammonia-induced cell death and GLS1 in gastric adenocarcinoma: implications for prognosis and therapeutic strategies.","authors":"Bing Du, Jiantao Dong, Qingmin Gao, Zhaoqiang Yin, Junping Yang, Shaowei Ma, Chunyi Song, Huan Ren, Zixin Yang","doi":"10.1186/s12935-025-03982-w","DOIUrl":"10.1186/s12935-025-03982-w","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer, primarily manifested as gastric adenocarcinoma (STAD), remains one of the leading causes of cancer-related deaths worldwide. Ammonia-induced cell death (AID), a newly discovered form of cell death, has gained attention due to its unique mechanisms, including lysosomal alkalinization and mitochondrial dysfunction. However, the role of AID in STAD, particularly its impact on immune regulation and patient prognosis, remains unclear.</p><p><strong>Methods: </strong>This study integrated bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data. The Seurat package was used for single-cell gene expression analysis, clustering different cell types, and AID scoring. CellChat software analyzed the ligand-receptor interactions between immune cell subtypes. Differential expression analysis (DEGs) and GO/KEGG enrichment identified key genes associated with AID. We constructed a prognostic risk model based on these findings. Immune cell infiltration was analyzed using the \"GSVA\" and \"xCell\" packages. In vitro experiments were conducted on HGC-27 and MKN45 gastric cancer cell lines, where GLS1 was knocked down using siRNA to assess the effects on cell proliferation, migration, invasion, and lysosomal function. Additionally, drug sensitivity tests were used to evaluate the impact of GLS1 overexpression on resistance to various anticancer drugs.</p><p><strong>Results: </strong>Single-cell clustering analysis revealed that T cells had significantly higher ammonia-induced cell death (AID) scores, leading to the classification of cells into high-AID and low-AID groups. Gene expression analysis and pathway enrichment showed significant enrichment in lysosomal and mitochondrial pathways, consistent with known AID mechanisms. A prognostic risk model based on five key genes (C1QA, MARCKSL1, GLS1, N4BP2L2, and CD68) effectively classified patients into high-risk and low-risk groups, with the high-risk group showing stronger immune cell infiltration, including CD4 + and CD8 + T cells, dendritic cells, and macrophages. Among the model genes, GLS1 was identified as the most significant prognostic factor, the strongest risk factor, and the most central gene in the interaction network. In vitro experiments showed that GLS1 inhibition led to increased ammonia levels, elevated lysosomal pH, and reduced lysosomal function, thereby enhancing AID expression. Furthermore, GLS1 overexpression significantly promoted cell proliferation, migration, and tumor growth. Finally, gastric cancer cells with GLS1 overexpression exhibited resistance to multiple anticancer drugs, highlighting the potential value of GLS1 as a therapeutic target.</p><p><strong>Conclusion: </strong>The AID model is a promising biomarker for accurately determining survival and predicting the effectiveness of immunotherapy in STAD patients. GLS1 plays a crucial role in driving tumor proliferation and migration and may act as a potential tumor biomarker of STAD.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"342"},"PeriodicalIF":6.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic potentiation of 5-fluorouracil by HDAC inhibitor quisinostat enhances antitumor effects in colorectal cancer.","authors":"Gizem Calibasi-Kocal, Hasan Kurter, Eylem Doga Nartas, Ender Berat Ellidokuz, Yasemin Basbinar","doi":"10.1186/s12935-025-03992-8","DOIUrl":"10.1186/s12935-025-03992-8","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"340"},"PeriodicalIF":6.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial electron transport chain gene-based prognostic model identifies SDHB as a key regulator of low-grade glioma progression and therapeutic target.","authors":"Yang Li, Qing Liu, Jun Su, Liangqi Jiang, Zhen Li, Hao Peng","doi":"10.1186/s12935-025-03958-w","DOIUrl":"10.1186/s12935-025-03958-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Low-grade gliomas (LGG) are a heterogeneous category of brain tumors characterized by a variable clinical course, frequently associated with unfavorable prognosis and therapeutic challenges. Understanding the molecular mechanisms underlying LGG progression is crucial for improving prognosis and therapeutic strategies. This study integrates single-cell RNA sequencing and bioinformatics to explore the role of METCGs (mitochondrial electron transport chain genes) in LGG and construct a predictive model for prognosis, and through in vitro experiments, the feasibility of this model was validated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We analyzed 5,691 cells and 22,947 genes from the GSE117891 dataset. Using cell marker genes from the CellMarker 2.0 database and classical markers, we identified four distinct cell types: oligodendrocytes, T cells, astrocytes, and microglial cells. The METCGs profiles were calculated using various algorithms, including AUCell, UCell, ssGSEA, and others. Differentially expressed genes (DEGs) were identified and enriched for relevant pathways. Machine learning algorithms were employed to construct a prognostic risk model based on five selected METCGs. The model was validated using independent LGG cohorts. Biological pathway analyses, immune infiltration profiles, and potential drug targets were also explored. To validate the reliability of this model through experiments, functional experiments, including Blue native Page (BN-Page), western blotting, immunofluorescence, and cell viability assays, were conducted to validate SDHB expression and its role in LGG progression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Astrocytes exhibited the highest METCG scores, indicating their central role in mitochondrial energy regulation. The prognostic model, constructed using the StepCox[forward] + plsRcox approach, included five genes: SDHB, SDHC, SLC25A27, UQCRB, and NDUFA13. The model demonstrated high prognostic accuracy with an average C-index of 0.67 and successfully stratified LGG patients into low- and high-risk groups. High-risk patients had worse survival outcomes, with significant differences observed in KEGG pathways, immune infiltration, and metabolic processes. The low-risk group exhibited higher immune cell infiltration, including follicular helper T and monocyte cells. AZD1208_1449 was identified as a potential drug targeting high-risk patients. Additionally, SDHB expression was significantly higher in LGG cells, and knockdown of SDHB inhibited cell proliferation and invasion, supporting its role in tumor progression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study provides a comprehensive analysis of METCGs in LGG and develops a robust prognostic model for patient stratification. SDHB, a key subunit of Complex II, plays a crucial role in mitochondrial function and tumor progression. Our findings suggest that he high expression of SDHB in LGG contributes to maintaining elevated SDH and Complex II activity, e","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"343"},"PeriodicalIF":6.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}