Cancer Cell International最新文献

{"title":"Palmitoylation regulators drive the progression of clear cell renal cell carcinoma through Inhibition of cuproptosis: insights into the role of ZDHHC18.","authors":"Wei Xu, Xiao-Chao Chen, Yang Wang, Jian-Chun Chen, Zhi-Jun Cao, Ru Huang, Chao Chen, Dao-Rong Hou, Min-Jun Jiang, Chen Xu","doi":"10.1186/s12935-025-03882-z","DOIUrl":"10.1186/s12935-025-03882-z","url":null,"abstract":"<p><strong>Background: </strong>Protein palmitoylation is a reversible post-translational modification that increases protein hydrophobicity, which can affect protein localization, stability, and function. Although palmitoylation is frequently observed in various cancers, the specific mechanisms by which it influences clear cell renal cell carcinoma (ccRCC) are still not well understood.</p><p><strong>Methods: </strong>This study used transcriptome expression profiles and clinical characteristics of clear cell renal cell carcinoma (ccRCC) obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Kaplan-Meier (KM) survival analysis was performed to evaluate patient survival. Consensus clustering was applied to identify tumor palmitoylation patterns. A total of 101 different machine learning methods were used to develop predictive models. Functional enrichment analyses were conducted using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Variation Analysis (GSVA).</p><p><strong>Results: </strong>Of the 34 prognosis-related palmitoylation-related genes (PRGs), 29 were used to cluster patients in the TCGA-KIRC cohort, leading to the identification of four palmitoylation clusters. We developed a risk model and a nomogram based on palmitoylation scores to enhance risk classification. Functional analysis indicated that high-risk patients exhibited disrupted fatty acid metabolism. Correlation analysis identified ZDHHC18 as a potential hub gene associated with impaired fatty acid metabolism and cuproptosis. Finally, we validated the role of ZDHHC18 in ccRCC proliferation through in vitro experiments.</p><p><strong>Conclusion: </strong>Our research demonstrated that PRGs play a crucial role in the development of clear cell renal cell carcinoma (ccRCC). A nomogram based on palmitoylation scores may accurately predict the prognosis of ccRCC patients. Furthermore, the palmitoylation regulator ZDHHC18 affects cuproptosis in ccRCC, which in turn impacts patient survival.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"230"},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473973","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 ADAMTS2 metalloproteinase inhibits tumor growth by regulating the innate immune system.","authors":"Loïc Joannes, Laura Dupont, Louis Stock, Esther Arpigny, Pascale Hubert, Marie Ancion, Margaux Luyckx, Joan Abinet, Wen Peng, Didier Calaldo, Agnes Noel, Thomas Marichal, Michael Herfs, Christophe Deroanne, Alain Colige","doi":"10.1186/s12935-025-03880-1","DOIUrl":"10.1186/s12935-025-03880-1","url":null,"abstract":"<p><strong>Background: </strong>ADAMTS2 is a metalloproteinase known to be implicated in collagen maturation and regulation of (lymph)angiogenesis. As these properties are likely to alter tumor progression, we aimed to assess the overall impact of ADAMTS2 on cancer development.</p><p><strong>Methods and results: </strong>Using publicly available human cancer datasets, we found that high expression of ADAMTS2 in primary tumors is associated with poor prognosis across various cancer types. Similar analyses were repeated, but this time using the ratio of ADAMTS2 on COL1A1 expression to take into account potential biases due to the involvement of ADAMTS2 in collagen fibril formation. Remarkably, these data indicate that patients with a high ADAMTS2/COL1A1 ratio exhibit an improved overall survival rate, suggesting that ADAMTS2 may inhibit cancer progression by a mechanism independent of collagen accumulation. This hypothesis was evaluated in vivo using ADAMTS2-KO mice and different tumor models characterized by the absence or presence of tumor collagen accumulation, as in MMTV-PyMT mice which develop spontaneous desmoplastic mammary tumors. In all the models, the growth of primary tumors was strongly increased in ADAMTS2-KO mice versus their wild type counterparts, confirming that ADAMTS2 displays anti-tumor properties. In stark contrast, the spread of lung metastases from mammary tumors was virtually prevented in ADAMTS2-KO mice, showing a dual role of ADAMTS2, either beneficial or detrimental, at different stages of cancer progression. Additional investigations, notably by FACS and single cell sequencing, showed that the effect of ADAMTS2 on primary tumors does not result from a direct effect on cancer cells, but rather from modifications in the intratumor innate immune system which becomes more immunosuppressive in the absence of ADAMTS2.</p><p><strong>Conclusion: </strong>We have shown that ADAMTS2 suppresses tumor growth by inhibiting the progressive establishment of an immunosuppressive microenvironment. Conversely, its presence allows efficient formation of lung metastases. These data identify ADAMTS2 as a cancer regulator with antagonistic functions, limiting initial progression but promoting efficient metastatic dissemination.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"229"},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473974","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":"Correlation between the use of dried Toad skin-radix clematidis and the development of intestinal dysbiosis and colorectal cancer.","authors":"Xue-Yan Wang, Li-Jun Pan, Bing Yang, Yang Liu, Dong-Xin Tang","doi":"10.1186/s12935-025-03861-4","DOIUrl":"10.1186/s12935-025-03861-4","url":null,"abstract":"<p><strong>Objective: </strong>To examine the impact of different intestinal microbiota conditions on the absorption of couplet medicines (dried toad skin and radix clematidis) into the bloodstream, and to evaluate the therapeutic effects of drug-containing plasma, produced under different intestinal microbiota conditions, on colorectal cancer HT-29 cells.</p><p><strong>Methods: </strong>In Experiment I, after the pseudo-sterile rat model was established, intragastric administration was performed. Explore the influence of different states of intestinal bacteria on rat organ coefficients, intestine bacteria, plasma metabolites, and so on. In Experiment II, the HT-29 cells of colon cancer were given to each group of drug-containing plasma for intervention to explore the intervention effect of HT-29-cell plasma produced under the influence of different states of intestinal bacteria.</p><p><strong>Results: </strong>Pseudo-sterile conditions can affect the body weight, organ coefficients, and immune cell ratios of rats, leading to dysbiosis in various segments of their intestinal microbiota. After administering traditional Chinese medicine under pseudo-sterile conditions, the immune cell ratios in rats returned to normal, and the dysbiosis in the intestinal microbiota improved. There were 271 differential metabolites in the plasma between the groups. Cellular experiments indicate that plasma containing drugs obtained under normal gut microbiota conditions can significantly inhibit the proliferation and migration of HT-29 cells (p < 0.01), while the inhibitory effect of plasma containing drugs obtained under dysbiotic gut microbiota conditions is reduced (p < 0.05).</p><p><strong>Conclusion: </strong>There is a bidirectional regulatory effect between the gut microbiota and the core medicinal pair. On one hand, dysbiosis weakens the efficacy of the medication. Dysbiosis can affect the blood components of the core medicinal pair. Compared to the drug-containing plasma produced under normal gut microbiota conditions, the drug-containing plasma produced under dysbiosis conditions has a reduced inhibitory effect on the proliferation of HT-29 cells. On the other hand, the drug repairs certain functions of the microbiota. After the drug enters the intestine, it exerts a positive regulatory effect on the dysbiosis of the intestinal microbiota in rats, partially improving the dysbiosis caused by antibiotics, restoring the balance of CD3+, CD4+, and CD8 + ratios in rats, and partially restoring the anticancer activity of drug-containing plasma.</p><p><strong>Clinical trial number: </strong>not applicable.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"228"},"PeriodicalIF":5.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367922","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 physical activity and epigenetic changes in colorectal cancer prevention.","authors":"Yu Sun, Ooi Boon Keat, Sogand Rajabi","doi":"10.1186/s12935-025-03872-1","DOIUrl":"10.1186/s12935-025-03872-1","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"227"},"PeriodicalIF":5.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367923","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":"LINC00601 promotes the progression of glioma via the p-STAT3 signaling pathway.","authors":"Chao Ma, Linqi Wang, Renwu Zhang, Tong Li, Peng Li, Yuxiang Ding, Dejun Wu, Yinyan Wang","doi":"10.1186/s12935-025-03735-9","DOIUrl":"10.1186/s12935-025-03735-9","url":null,"abstract":"<p><strong>Background: </strong>Gliomas, the most common malignant tumors of the central nervous system, primarily originate from glial cells, which support nerve cells. Due to their high malignancy and aggressiveness, gliomas frequently result in poor prognoses. Increasing evidence suggests that long non-coding RNAs (lncRNAs) have diverse roles in cancer; however, their specific functions in gliomas remain poorly understood. This study elucidates the roles and potential mechanisms of the lncRNA LINC00601 in glioma.</p><p><strong>Methods: </strong>Bioinformatics analysis was utilized to identify the expression of LINC00601 and to perform related survival analysis. Glioma cells were transfected with a control vector small interfering RNA (si-NC) or small interfering RNA LINC00601 (si-LINC00601). Cell proliferation was evaluated using the CCK-8 assay and plate colony formation assay. Cell migration and invasion were assessed using the Transwell assay. Protein expression was detected by Western blot analysis, and lncRNA levels were measured using quantitative real-time PCR (qRT-PCR).</p><p><strong>Results: </strong>Bioinformatics analysis revealed that LINC00601 is associated with the pathological grade and prognosis of glioma, as evidenced by data from the TCGA and CGGA databases. In vivo experiments showed that LINC00601 knockdown inhibits the proliferation, migration, and invasion of U251 and U87 cells. Based on sequencing and Western blot results, this effect is thought to be linked to changes in Phosphorylated Signal Transducer and Activator of Transcription 3 (p-STAT3) expression. Additionally, in vitro knockdown of LINC00601 has been shown to inhibit glioma growth.</p><p><strong>Conclusions: </strong>LINC00601, which facilitates glioma progression by modulating the p-STAT3 signaling pathway, could serve as a potential molecular target for glioma therapy.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"220"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339908","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":"Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression.","authors":"Yang-Hsiang Lin, Ming-Wei Lai, Chau-Ting Yeh, Wey-Ran Lin","doi":"10.1186/s12935-025-03849-0","DOIUrl":"10.1186/s12935-025-03849-0","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) integration, the HBx protein (and its mutants), and covalently closed circular DNA (cccDNA) are critical for HBV replication, packaging, and transmission to new host cells. Although nucleos(t)ide analogs (NAs) are a class of antiviral drugs that effectively suppress HBV replication, they do not eliminate cccDNA. This persistent cccDNA, often referred to as an \"invisible bullet\", plays a pivotal role not only in the horizontal transmission of HBV but also within the context of hepatocellular carcinoma (HCC). Growing evidence reveals that noncoding RNAs (ncRNAs) are deeply involved in cancer progression, as well as the HBV life cycle and related pathogenesis, including liver inflammation, fibrosis, and HCC. This involvement occurs through various mechanisms, as ncRNAs regulate gene transcription, act as miRNA sponges, modulate signaling pathways, and influence downstream effects. These functions depend on the proper formation of RNA structures, which are critical for maintaining the biological activity of ncRNAs. The structure of RNAs appears to play a pivotal role in their functional capacity. Moreover, both ncRNAs and viral nucleotides contribute to G-quadruplex structure formation, which is essential for the HBV life cycle and cancer progression. In this review, we provide an updated overview of the mechanisms by which key ncRNAs mediate HBV/cccDNA actions in HCC progression and focus on their roles in gene expression and structural formation/modification.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"224"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339910","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":"Prognostic and therapeutic potential of disulfidptosis-related genes in colon adenocarcinoma: a comprehensive multi-omics study.","authors":"Ye Song, Haoran Zhu, Junyang Wei, Shanxue Yin","doi":"10.1186/s12935-025-03855-2","DOIUrl":"10.1186/s12935-025-03855-2","url":null,"abstract":"<p><strong>Background: </strong>Disulfidptosis-related genes (DRGs) have emerged as key players in the prognosis of colon cancer(CC) and hold promise as potential therapeutic targets. This study systematically evaluates their prognostic significance and explores their potential for therapeutic intervention in colon adenocarcinoma.</p><p><strong>Methods: </strong>Colon adenocarcinoma(COAD) samples were categorized based on DRG expression to analyze differences in the immune landscape across molecular subtypes. Variations between high-risk (HRG) and low-risk (LRG) groups and changes in cell population dynamics across different stages were examined. The expression patterns of Diaphanous-Related Formin 1 (DIAPH1) and NADH: Ubiquinone Oxidoreductase Subunit B10 (NDUFB10), key components of the prognostic model, were assessed during T cell development. The model was validated using external datasets, and single-cell analysis was performed to investigate spatial distribution differences in tumor-infiltrating cell populations.</p><p><strong>Results: </strong>DRGs were critical in modulating T cell differentiation in COAD. DIAPH1 and NDUFB10 showed significant fluctuations during T cell development, indicating their involvement in immune regulation. Single-cell analysis revealed distinct spatial distribution patterns between T cells and epithelial cells. The ProjecTILs algorithm identified a higher proportion of Th1 cells, while Graph Convolutional Network (GCN) analysis showed no significant differences in T cell subtype proportions across different phenotypes. In vitro experiments further demonstrated that the knockdown of DIAPH1 and NDUFB10 in T cells effectively inhibited tumor proliferation.</p><p><strong>Conclusion: </strong>The DRG-based prognostic model demonstrated strong predictive power in COAD, highlighting the potential of DRGs as therapeutic targets. These findings provide a solid foundation for developing novel treatment strategies targeting disulfide ptosis pathways in CC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"226"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339911","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 single-cell and bulk RNA sequencing data unveils antigen-presenting and processing fibroblasts and establishes a predictive model in gastric cancer.","authors":"Chenggang Zhang, Fangqi Chen, Jie Li, Yixuan He, Juan Sun, Zicheng Zheng, Guanmo Liu, Yihua Wang, Weiming Kang, Xin Ye","doi":"10.1186/s12935-025-03878-9","DOIUrl":"10.1186/s12935-025-03878-9","url":null,"abstract":"<p><strong>Background: </strong>Antigen-presenting and processing fibroblasts (APPFs) have emerged as pivotal regulators of antitumor immunity. However, the predictive value of APPF-related genes (APPFRGs) in the prognosis and tumor immune status of gastric cancer (GC) remains largely unexplored.</p><p><strong>Methods: </strong>Bioinformatics analysis was conducted using single-cell and bulk RNA sequencing datasets of GC retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The APPFs were identified using AUCell algorithm based on APP-associated genes obtained from the InnateDB database. CellChat algorithm was utilized to evaluate interactions between cells. The non-negative matrix factorization (NMF) clustering analysis was performed to identify APPF-related subgroups based on TCGA‑stomach adenocarcinoma cohort. LASSO and multivariate Cox regression analysis were conducted to establish the predictive model. Immunohistochemistry of GC tissue microarrays was performed to validate the model.</p><p><strong>Results: </strong>Compared to non-APPFs, APPFs exhibited more interactions with myeloid cells, endothelial cells, and lymphocytes via MHC-II signaling network. The two APPF-related subgroups clustered by NMF demonstrated significant differences in prognosis and immune cell infiltration. Five APPFRGs (CPVL, ZNF331, TPP1, LGALS9, TNFAIP2) were identified to establish the predictive model and stratify GC patients based on risk score. The prognosis was significantly different between the two risk groups and was validated using GEO datasets. A nomogram that efficiently predicted the overall survival of GC patients was established by integrating the risk score with age, T stage, N stage, and M stage. Furthermore, the high-risk group exhibited reduced infiltration of activated CD4⁺ T cell and increased infiltration of Treg cells, higher resistance to chemotherapy and immunotherapy, and lower tumor mutation burden. Finally, the immunohistochemical results of GC tissue microarrays revealed higher expression of CPVL, ZNF331, and TPP1, and lower expression of LGALS9 and TNFAIP2 in GC compared to adjacent normal tissues. Additionally, higher risk score in GC samples was relevant with poor differentiation, positive nerve invasion, advanced T and TNM stages, and higher expression of FOXP3.</p><p><strong>Conclusions: </strong>APPFs may play an important role in the regulation of tumor immune microenvironment in GC and warrant further exploration. The predictive model based on APPFRGs effectively predicts the prognosis and tumor immune status of GC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"225"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339906","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":"MitCOM-based prognostic model identifies GLUD1 as a key suppressor of glioblastoma growth and invasion through regulation of mitochondrial structure and metabolism.","authors":"Yang Li, Chaoying Qin, Liangqi Jiang, Jun Su, Zhen Li, Qing Liu, Yuanbing Yao","doi":"10.1186/s12935-025-03875-y","DOIUrl":"10.1186/s12935-025-03875-y","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"222"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339909","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":"HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression.","authors":"Yang-Hsiang Lin, Ming-Wei Lai, Yu-De Chu, Kwang-Huei Lin, Chao-Wei Hsu, Rong-Nan Chien, Po-Heng Chuang, Chih-Lang Lin, Chau-Ting Yeh","doi":"10.1186/s12935-025-03873-0","DOIUrl":"10.1186/s12935-025-03873-0","url":null,"abstract":"<p><strong>Background: </strong>A number of effective antiviral agents for chronic hepatitis B are available worldwide, and these agents have exhibited satisfactory virologic suppression, but suboptimal responses still occur in some patients. We aimed to explore the contribution of long non-coding RNAs (lncRNAs) in mediating suboptimal responses in chronic hepatitis B patients, which remains to be fully elucidated.</p><p><strong>Methods: </strong>Cox regression models were used to analyze associations between suboptimal response and clinical factors. Hepatitis B virus X (HBx) gene was sequenced from entecavir-treated patients who developed hepatocellular carcinoma (HCC). Functional assays were conducted using Transwell assays, MTT assays, and xenograft model.</p><p><strong>Results: </strong>Suboptimal response was found to be a significant independent predictor of HCC development. Five of the six patients who developed HCC in the suboptimal response period were found to have HBx mutations (HBx-L100 insertion, HBx-G32R/K130M, HBx-Q87G/k130M/C143R, HBx-L123S, and HBx-H94Y/K130M). Overexpression of the HBx-H94Y/K130M mutation in HepG2.2.15 cells showed significantly increased cccDNA accumulation and enhanced cell migration compared to controls and other HBx mutants. RNA-seq analysis identified RPL13AP25 as a direct target of HBx-H94Y/K130M. RPL13AP25 was highly expressed in HCC tissues, and its elevated expression was associated with poor overall survival and enhanced cell motility and cccDNA accumulation both in vitro and in vivo. Mechanistically, both HBx-H94Y/K130M and RPL13AP25 enhanced the hyperphosphorylation of eIF4EBP1, leading to its dissociation from eIF4E, which subsequently enhances protein synthesis and ultimately contributes to HCC.</p><p><strong>Conclusions: </strong>The HBx-H94Y/K130M mutant, selected during the period of suboptimal virological response, appears to promote cccDNA accumulation, likely through the upregulation of RPL13AP25, which contributed to HCC progression.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"25 1","pages":"223"},"PeriodicalIF":5.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339907","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}