{"title":"Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.","authors":"Alina Chaplygina, Daria Zhdanova","doi":"10.31083/FBL44648","DOIUrl":"https://doi.org/10.31083/FBL44648","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial dynamics-the balance between fission, fusion, and mitophagy-are essential for maintaining cellular homeostasis and are increasingly implicated in the pathogenesis of Alzheimer's disease (AD).</p><p><strong>Methods: </strong>Here, we investigated the effects of targeted modulation of mitochondrial fission and fusion on mitochondrial morphology and metabolic status in primary hippocampal cultures derived from 5xFAD transgenic mice. Mitochondrial dynamics were modulated using the fission inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), the fusion promoter mitochondrial fusion promoter M1 (MFP M1), and exogenous zinc as a fission activator. We evaluated mitochondrial morphology, lipofuscin accumulation, beta-amyloid (Aβ42) levels, and reactive oxygen species (ROS). The general condition of the cultures was assessed morphologically using neuronal and astrocytic markers.</p><p><strong>Results: </strong>Modulating mitochondrial dynamics altered mitochondrial morphology, decreased Aβ42, lipofuscin, and ROS levels, and improved cellular organization. Treatments with MFP and Mdivi-1 promoted mitochondrial hyperfusion without complete network integration and were associated with reduced astrogliosis and increased neuronal density. In contrast, zinc induced dose-dependent mitochondrial fragmentation and astrocytic clasmatodendrosis, with lower concentrations enhancing Aβ clearance and higher concentrations inducing toxicity.</p><p><strong>Conclusions: </strong>Mitochondrial fusion and fission significantly influence lipofuscin and amyloid accumulation in 5xFAD cultures, underscoring their potential as therapeutic targets in neurodegenerative diseases. We propose that mitochondrial morphology acts as a key regulator of both cellular homeostasis and disease pathology.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44648"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chunyan Wang, Chanjuan Cui, Shengkai Huang, Mengyao Yu, Lili Wang, Hengwen Gong, Rui Qiao, Jun Ma
{"title":"Single-cell Sequencing Analysis Reveals Cell Subtypes With High Expression of Coagulation Factor 3 and Their Possible Roles in Pancreatic Ductal Adenocarcinoma.","authors":"Chunyan Wang, Chanjuan Cui, Shengkai Huang, Mengyao Yu, Lili Wang, Hengwen Gong, Rui Qiao, Jun Ma","doi":"10.31083/FBL44029","DOIUrl":"https://doi.org/10.31083/FBL44029","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a high incidence of thrombosis. Coagulation factor 3 (F3) plays a key role in initiating the coagulation pathway. This study identified cell subpopulations that highly express F3 and explored their potential roles in PDAC.</p><p><strong>Methods: </strong>This study evaluated 1837 patients with PDAC from two cancer hospitals between November 1, 2023, and November 30, 2024. The analyses included assessing coagulation and fibrinolysis indicators, and employing single-cell sequencing technology to examine the tumor microenvironment in freshly resected PDAC tissues. Findings were validated using the Gene Expression Omnibus database.</p><p><strong>Results: </strong>Over half of the patients (54.98%) with PDAC showed abnormal coagulation indicators. F3 mRNA and protein levels were higher in PDAC tissues than in normal tissues. This high F3 expression in PDAC was associated with a poor prognosis (<i>p</i> < 0.01). Analysis of 33,300 cells from freshly resected PDAC tissues showed high F3 expression in cancer-associated fibroblasts (CAFs) and ductal cells. Subsequent subtype analysis indicated that ductal cell 1 (tumor cells) and inflammatory CAFs (iCAFs) exhibited high F3 expression. Pseudotime trajectory analysis showed that iCAFs were prevalent in the earlier part of the pseudotime pathway. Notably, pathways associated with inflammation, phosphoinositide 3-kinase/Akt signaling, and coagulation and complement were significantly enriched in iCAFs. In addition, the interaction between iCAFs and tumor cells was regulated by growth factor receptor-ligand pairings. \"GSE212966\" and \"GSE197177\" data confirmed these results.</p><p><strong>Conclusion: </strong>The high expression of F3 in specific iCAF subtypes suggests a role in PDAC hypercoagulability and tumor progression. Targeting these iCAF subtypes could provide potential strategies for treating PDAC.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44029"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hailun Wang, Qiao Wang, Yandu He, Xuelu Pu, Yajun Li
{"title":"PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear-Mitochondrial Homeostatic Crosstalk.","authors":"Hailun Wang, Qiao Wang, Yandu He, Xuelu Pu, Yajun Li","doi":"10.31083/FBL45020","DOIUrl":"https://doi.org/10.31083/FBL45020","url":null,"abstract":"<p><strong>Background: </strong>Phosphatidylserine synthase 1 (PTDSS1) is a crucial enzyme involved in phospholipid synthesis. However, its role in the metabolic regulation of lung cancer remains unclear. This study hypothesized that PTDSS1 promotes lung cancer progression by regulating metabolic reprogramming through nuclear-mitochondrial crosstalk.</p><p><strong>Methods: </strong>PTDSS1's expression levels in lung cancer tissues and their correlation with patient prognosis were evaluated through bioinformatics analysis and immunohistochemistry. <i>In vitro</i> functional experiments, including cell proliferation, migration, invasion, and colony formation, were performed using PTDSS1-overexpressing lung cancer cell lines. Cellular glycolysis and mitochondrial oxidative phosphorylation levels were determined. PTDSS1's subcellular localization was investigated through cellular fractionation and immunofluorescence. Its regulatory interaction with pyruvate kinase M2 (<i>PKM2</i>) was examined. Expression levels of metabolism-related genes and mitochondrial dynamics markers were analyzed by qRT-PCR and Western blot.</p><p><strong>Results: </strong>PTDSS1 was significantly overexpressed in lung cancer tissues. High PTDSS1 expression correlated with poor patient prognosis. PTDSS1 enhanced lung cancer cell proliferation, migration, and invasion capabilities. Metabolically, PTDSS1 promoted aerobic glycolysis. Mitochondrial oxidative phosphorylation was suppressed. Nuclear-localized PTDSS1 showed enhanced effectiveness in driving glycolysis and malignant progression. Mechanistically, PTDSS1 may accelerate glycolysis through <i>PKM2</i> regulation. It may drive lung cancer progression through PKM2-mediated nuclear-mitochondrial homeostatic crosstalk.</p><p><strong>Conclusion: </strong>PTDSS1 functions as a multifunctional oncogene. It drives lung cancer progression through PKM2-mediated nuclear-mitochondrial homeostatic crosstalk. PTDSS1 represents a potential prognostic biomarker and therapeutic target.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"45020"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advances in Single-Cell RNA Sequencing: Applications and Mechanistic Insights in Haematopoietic Malignancies.","authors":"Yixin Guo, Shuang Wang, Xinyue Huang, Yanhua Zheng, Fang Liu, Xiaoxue Wang","doi":"10.31083/FBL39064","DOIUrl":"https://doi.org/10.31083/FBL39064","url":null,"abstract":"<p><p>Single-cell RNA sequencing (scRNA-seq) technology, also known as single-cell transcriptome sequencing, has become a key tool in biology and medicine, enabling deeper insights into cellular diversity and disease mechanisms. Since 2009 when scRNA-seq technology was first introduced, many technologies have been developed and improved, with a wide range of applications in haematopoietic malignancies, solid tumours, and other fields. These technologies have been used by researchers to map transcriptomes, study intra- and inter-cellular heterogeneity, investigate tumour microenvironments, analyse specific cellular subpopulations, and assist in clinical studies. This review categorises scRNA-seq on the basis of different single-cell amplification techniques, provides an overview of the principles of currently commonly used scRNA-seq techniques, discusses the application of scRNA-seq in the context of haematopoietic malignancies, and will hopefully play a role in the future development of single-cell sequencing technologies.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"39064"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Colchicine Only Inhibits in Higher Doses Hyperactivated NLRP3 Inflammasome-The Main Respondent for Complications in COVID-19 and Influenza.","authors":"Vanyo Mitev, Georgi Momekov","doi":"10.31083/FBL44744","DOIUrl":"https://doi.org/10.31083/FBL44744","url":null,"abstract":"<p><p>Despite the enormous theoretical progress, there is currently no effective treatment for the cytokine storm (CS) in COVID-19 and Influenza, which is due to hyperactivation of NOD-like receptor protein 3 inflammasome (NLRP3-I). According to our research, the only way to prevent or interrupt the CS is to administer high but safe doses of colchicine, which inhibits NLRP3-I/CS.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"44744"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Diagnostic Value of <i>CDO1</i> Promoter Methylation in Lung Cancer via Liquid Biopsy: A Systematic Review and Meta-Analysis.","authors":"Yuheng Yan, Ziyang Xu, Fangfang Liu, Yuhan Jia, Qian Chu, Xun Yuan","doi":"10.31083/FBL43987","DOIUrl":"https://doi.org/10.31083/FBL43987","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate cysteine dioxygenase 1 (<i>CDO1</i>) gene promoter methylation in circulating tumor DNA as a biomarker for the early diagnosis of lung cancer.</p><p><strong>Methods: </strong>Data up to June 5, 2025, across electronic databases (PubMed, Embase, Web of Science, and the China National Knowledge Infrastructure) were searched. The quality assessment tool for diagnostic accuracy studies-2 (QUADAS-2) checklist was used to assess the risk of bias in the incorporated studies. A random-effects model was employed to generate summary statistics for diagnostic accuracy, which included pooled sensitivity and specificity estimates, the diagnostic odds ratio (DOR), and a summary receiver operating characteristic curve. An exploration of heterogeneity sources was undertaken using meta-regression, followed by a sensitivity analysis to test the consistency of the results. Finally, Deek's funnel plot was generated to estimate publication bias, and the clinical feasibility was evaluated using Fagan's nomogram.</p><p><strong>Results: </strong>Seven relevant studies were included in this meta-analysis. No major concerns regarding the quality risk of the included studies were observed. The pooled diagnostic sensitivity, specificity, and DOR values of the <i>CDO1</i> promoter methylation for lung cancer were 0.63 (95% CI: 0.60-0.67), 0.78 (95% CI: 0.74-0.82), and 5.96 (95% CI: 4.06-8.74), respectively, and the area under curve was 0.7423. Statistical heterogeneity was observed in sensitivity (I<sup>2</sup> = 73%, <i>p</i> < 0.1), specificity (I<sup>2</sup> = 79.5%, <i>p</i> < 0.1), and DOR (I<sup>2</sup> = 42.9%, <i>p</i> < 0.1); however, variables such as the region, sample source, sample size, and detection method did not significantly affect heterogeneity (<i>p</i> > 0.05). The results were robust as the DOR was not overly influenced by the deletion of any single study. No publication bias was observed in this study (<i>p</i> = 0.74). Additionally, under a pre-test probability of 20%, the positive post-test probability of <i>CDO1</i> promoter methylation in lung cancer was predicted to be 42%. PROSPERO CRD420251131665, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251131665.</p><p><strong>Conclusion: </strong>The detection of <i>CDO1</i> promoter methylation in biofluids represents a promising tool for the early diagnosis of lung cancer. Future studies should focus on improving detection methodologies and investigating combinational strategies with high accuracy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"43987"},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tetraspanin-Mediated ADAM10 Regulation in Sepsis and Potential Therapeutic Implications.","authors":"Meiting Yang, Yao Lin, Yufu He, Shuanglin Liao, Yuting Qin, Lizhen Liu, Junbing He, Yiming Shao","doi":"10.31083/FBL39386","DOIUrl":"https://doi.org/10.31083/FBL39386","url":null,"abstract":"<p><p>Excessive inflammatory responses in sepsis result in multiorgan dysfunction, with the majority of these responses being modulated by the activity of a disintegrin and metalloproteinase 10 (ADAM10). Due to the widespread distribution of ADAM10 and its numerous substrates, therapies targeting ADAM10 will have a range of physiological effects, including modulating inflammation, but may also cause toxic side effects. Precise therapeutic targets for regulating ADAM10 in specific diseases are needed. In several studies, tetraspanin family members have been identified as regulators of specific proteins, including ADAM10. In various cell types, the identical tetraspanin exhibits distinct effects on the regulation of ADAM10, indicating that tetraspanins possess cell-specific roles in modulating ADAM10. Furthermore, the interaction of diverse tetraspanins with ADAM10 results in the cleavage of various substrates. In this review, we provide a summary of the diverse tetraspanins that are currently recognized to interact with ADAM10 to identify potential new targets for regulating ADAM10 in sepsis.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"39386"},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xian Cheng, Xu Han, Haiyin An, Jialiang Fan, Junyi Li, Ting Xiao, Lin Feng, Shujun Cheng
{"title":"LINC01605 Suppresses Esophageal Squamous Carcinogenesis by Regulating Squamous Cell Differentiation, Proliferation, and Migration.","authors":"Xian Cheng, Xu Han, Haiyin An, Jialiang Fan, Junyi Li, Ting Xiao, Lin Feng, Shujun Cheng","doi":"10.31083/FBL42805","DOIUrl":"https://doi.org/10.31083/FBL42805","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) develops through a multistage process in which normal epithelium transitions into intraepithelial neoplasia and ultimately into invasive carcinoma. Elucidating the molecular changes and functional roles of key genes during this progression is critical for understanding the mechanisms underlying this malignant transformation.</p><p><strong>Methods: </strong>Transcriptomic profiles of 12 normal esophageal tissues, 5 intraepithelial neoplasia tissues, and 7 ESCC tissues were analyzed via microarray. Stage-specific transcriptomic changes were systematically compared to delineate the phenotypic evolution that occurs during carcinogenesis, with a particular focus on identifying pivotal genes that regulate the precancerous-to-malignant transition. The candidate gene <i>LINC01605</i> was further examined via the following approaches: (1) bioinformatics-based characterization of its tumor-associated functions using Genotype-Tissue Expression Project (GTEx) normal tissue and The Cancer Genome Atlas Program (TCGA) ESCC transcriptome; (2) functional validation in ESCC cell lines in which the gene was silenced or overexpressed <i>in vitro</i>; and (3) mechanistic exploration of RNA-binding partners via streptavidin bead-based RNA pull-down assays.</p><p><strong>Results: </strong>Multistage transcriptomic analysis revealed the progressive acquisition of cancer hallmarks during ESCC development. The transition from precancerous lesions to invasive carcinoma was characterized by epithelial dedifferentiation, extracellular matrix remodeling, and angiogenesis. <i>LINC01605</i>, which is a long noncoding RNA (lncRNA), was downregulated during this transition. GTEx revealed that <i>LINC01605</i> was specifically expressed in the squamous epithelium of the esophagus and that its expression was negatively correlated with histological grade in the TCGA-ESCC dataset. Samples with high <i>LINC01605</i> expression and those with low <i>LINC01605</i> expression in the TCGA dataset exhibited significant functional differences in epithelial cell differentiation, proliferation, and migration, as well as in the extracellular matrix. Knocking down <i>LINC01605</i> increased proliferation and migration in both the normal immortalized esophageal epithelial cell line NE3 and the ESCC cell line KYSE180. Conversely, the overexpression of <i>LINC01605</i> isoforms suppressed these malignant phenotypes. RNA pull-down revealed potential interactions between LINC01605 and aurora kinase B (AURKB), which are components of the chromosomal passenger complex (CPC), suggesting its involvement in regulating the cell cycle.</p><p><strong>Conclusion: </strong><i>LINC01605</i> functions as a tumor suppressor in ESCC by maintaining squamous cell differentiation and inhibiting proliferation and migration. <i>LINC01605</i> downregulation facilitates malignant transformation during esophageal carcinogenesis.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"42805"},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tao Yang, Jingjing Dai, Junlan Zhou, Yuyun Shao, Xiao Wang, Jiaying Zhao, Jun Li, Ping Shi, Longfeng Jiang
{"title":"Notch1 Inhibition Exacerbates APAP-Induced Liver Injury via β-Catenin and Macrophage Polarization.","authors":"Tao Yang, Jingjing Dai, Junlan Zhou, Yuyun Shao, Xiao Wang, Jiaying Zhao, Jun Li, Ping Shi, Longfeng Jiang","doi":"10.31083/FBL43853","DOIUrl":"https://doi.org/10.31083/FBL43853","url":null,"abstract":"<p><strong>Background: </strong>Notch1 signaling regulates innate immune-mediated inflammation in acute liver injury (ALI). However, the precise mechanism by which Notch1 governs macrophage polarization during ALI remains poorly understood.</p><p><strong>Methods: </strong>Wild-type (WT) mice received DAPT (10 mg/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the β-catenin inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative real-time PCR (RT-PCR), and western blotting.</p><p><strong>Results: </strong>Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the β-catenin/glycogen synthase kinase 3 beta (GSK3β) signaling pathway emerged as a pivotal regulator of macrophage polarization.</p><p><strong>Conclusions: </strong>Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via β-catenin signaling. These findings highlight the Notch1-β-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"43853"},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chen Fang, Chaoxing Liu, Rong Qi, Jiabin Ding, Ting Luo, Feng Yu, Guohua Zhang, Chao Shi, Daya Luo, Feng Qiu
{"title":"Integrated Analysis of Single-cell and Bulk-RNA Sequencing Data to Identify Redox-related Genes as Prognostic Biomarkers and Therapeutic Targets of Lung Adenocarcinoma With Osimertinib Resistance.","authors":"Chen Fang, Chaoxing Liu, Rong Qi, Jiabin Ding, Ting Luo, Feng Yu, Guohua Zhang, Chao Shi, Daya Luo, Feng Qiu","doi":"10.31083/FBL40454","DOIUrl":"https://doi.org/10.31083/FBL40454","url":null,"abstract":"<p><strong>Background: </strong>Acquired resistance limits the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD). Redox homeostasis is crucial for LUAD progression. However, how redox imbalance interacts with the tumor microenvironment (TME) to drive osimertinib resistance (OR) remains unclear.</p><p><strong>Methods: </strong>The single-cell RNA sequencing (scRNA-seq) data GSE243562 were combined with the Cancer Genome Atlas (TCGA)-LUAD transcriptomes to map the TME cell population heterogeneity in osimertinib-resistant LUAD. Through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regularization, a prognostic signature founded on redox-related genes (RRGs) was built. Therapeutic compounds targeting these signature genes were prioritized by molecular docking. Their expression patterns were subsequently validated <i>in vitro</i>.</p><p><strong>Results: </strong>Cancer-associated fibroblasts (CAFs) were central hubs in the TME of osimertinib-resistant LUAD, exhibiting enhanced intercellular communication. Computational profiling identified 10 differentially expressed RRGs, predominantly enriched in CAFs. Using a six-gene signature comprising <i>AGER</i>, <i>CYP2J2</i>, <i>FMO2</i>, <i>HSPA1B</i>, <i>SOD3</i>, and <i>VASN</i>, we categorized LUAD patients into separate risk categories. High-risk patients showed significantly reduced survival, an immunosuppressive status, and a higher tumor mutation burden (<i>p</i> < 0.05). The overexpression of these six genes was confirmed in OR cells. Critically, inhibiting SOD3 restored osimertinib sensitivity <i>in vitro</i> (<i>p</i> < 0.05). Clinically, SOD3 expression was lower in patients sensitive to third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) than in those with resistant disease.</p><p><strong>Conclusions: </strong>Targeting CAFs represents a promising strategy to overcome osimertinib resistance. Our six-gene redox signature offers a clinical framework for patient risk stratification and novel therapeutic strategy design. Future work will explore these targets to develop new treatments for LUAD.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"30 9","pages":"40454"},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}