{"title":"NFS1的下调和奥沙利铂联合作用通过Caspase-3/GSDME途径诱导胃癌细胞焦亡","authors":"Weiwei Jiang, Miao Zhang, Nan Hu, Chenxi Mao, Yiqian Han, Luming Zhao, Mingtong Liang, Fenglei Wu","doi":"10.2174/0113862073386878250801103600","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to elucidate the role of NFS1 in gastric cancer (GC) prognosis, pyroptosis, and oxaliplatin chemosensitivity, and to explore its interaction with the MAPK signaling pathway.</p><p><strong>Methods: </strong>GC mRNA expression and clinical survival data were obtained from The Cancer Genome Atlas Gastric Adenocarcinoma (TCGA-STAD). Kaplan-Meier analysis assessed the prognostic significance of NFS1. R software facilitated NFS1 expression analysis and KEGG pathway enrichment. Pyroptosis was evaluated using Cell Counting Kit-8, flow cytometry, and morphological analysis. Western blotting quantified pyroptosis-related protein expression. RNA sequencing libraries were prepared and sequenced on the Illumina platform.</p><p><strong>Results: </strong>Oxaliplatin treatment significantly reduced cell viability and induced pyroptosis, which was markedly attenuated by GSDME deficiency. Oxaliplatin activated caspase-3 and cleaved GSDME, effects that were reversed by the caspase-3 inhibitor Z-DEVD. NFS1 knockdown enhanced GSDME and caspase-3 cleavage, increasing pyroptosis (PI and Annexin-V doublepositive cells) compared to controls. KEGG analysis of RNA sequencing and TCGA data highlighted the MAPK signaling pathway. Western blotting confirmed that oxaliplatin combined with NFS1 knockdown suppressed MAPK pathway proteins.</p><p><strong>Discussion: </strong>The caspase-3/GSDME axis mediates oxaliplatin-induced GC pyroptosis. High NFS1 expression inhibits GSDME activation, promotes MAPK protein activation, and reduces oxaliplatin sensitivity. These findings suggest that the caspase-3/GSDME pathway offers a novel mechanism for oxaliplatin's antitumor effects. NFS1 may serve as an independent prognostic biomarker in GC, influencing disease progression through MAPK regulation.</p><p><strong>Conclusion: </strong>NFS1 is a promising therapeutic target for gastric cancer, especially in the study of oxaliplatin-based chemotherapy in combination with a treatment regimen that triggers pyroptosis.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Knockdown of NFS1 and Oxaliplatin Combination Induces Pyroptosis via the Caspase-3/GSDME Pathway in Gastric Cancer Cells.\",\"authors\":\"Weiwei Jiang, Miao Zhang, Nan Hu, Chenxi Mao, Yiqian Han, Luming Zhao, Mingtong Liang, Fenglei Wu\",\"doi\":\"10.2174/0113862073386878250801103600\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>This study aimed to elucidate the role of NFS1 in gastric cancer (GC) prognosis, pyroptosis, and oxaliplatin chemosensitivity, and to explore its interaction with the MAPK signaling pathway.</p><p><strong>Methods: </strong>GC mRNA expression and clinical survival data were obtained from The Cancer Genome Atlas Gastric Adenocarcinoma (TCGA-STAD). Kaplan-Meier analysis assessed the prognostic significance of NFS1. R software facilitated NFS1 expression analysis and KEGG pathway enrichment. Pyroptosis was evaluated using Cell Counting Kit-8, flow cytometry, and morphological analysis. Western blotting quantified pyroptosis-related protein expression. RNA sequencing libraries were prepared and sequenced on the Illumina platform.</p><p><strong>Results: </strong>Oxaliplatin treatment significantly reduced cell viability and induced pyroptosis, which was markedly attenuated by GSDME deficiency. Oxaliplatin activated caspase-3 and cleaved GSDME, effects that were reversed by the caspase-3 inhibitor Z-DEVD. NFS1 knockdown enhanced GSDME and caspase-3 cleavage, increasing pyroptosis (PI and Annexin-V doublepositive cells) compared to controls. KEGG analysis of RNA sequencing and TCGA data highlighted the MAPK signaling pathway. Western blotting confirmed that oxaliplatin combined with NFS1 knockdown suppressed MAPK pathway proteins.</p><p><strong>Discussion: </strong>The caspase-3/GSDME axis mediates oxaliplatin-induced GC pyroptosis. High NFS1 expression inhibits GSDME activation, promotes MAPK protein activation, and reduces oxaliplatin sensitivity. These findings suggest that the caspase-3/GSDME pathway offers a novel mechanism for oxaliplatin's antitumor effects. NFS1 may serve as an independent prognostic biomarker in GC, influencing disease progression through MAPK regulation.</p><p><strong>Conclusion: </strong>NFS1 is a promising therapeutic target for gastric cancer, especially in the study of oxaliplatin-based chemotherapy in combination with a treatment regimen that triggers pyroptosis.</p>\",\"PeriodicalId\":10491,\"journal\":{\"name\":\"Combinatorial chemistry & high throughput screening\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Combinatorial chemistry & high throughput screening\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0113862073386878250801103600\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Combinatorial chemistry & high throughput screening","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0113862073386878250801103600","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Knockdown of NFS1 and Oxaliplatin Combination Induces Pyroptosis via the Caspase-3/GSDME Pathway in Gastric Cancer Cells.
Introduction: This study aimed to elucidate the role of NFS1 in gastric cancer (GC) prognosis, pyroptosis, and oxaliplatin chemosensitivity, and to explore its interaction with the MAPK signaling pathway.
Methods: GC mRNA expression and clinical survival data were obtained from The Cancer Genome Atlas Gastric Adenocarcinoma (TCGA-STAD). Kaplan-Meier analysis assessed the prognostic significance of NFS1. R software facilitated NFS1 expression analysis and KEGG pathway enrichment. Pyroptosis was evaluated using Cell Counting Kit-8, flow cytometry, and morphological analysis. Western blotting quantified pyroptosis-related protein expression. RNA sequencing libraries were prepared and sequenced on the Illumina platform.
Results: Oxaliplatin treatment significantly reduced cell viability and induced pyroptosis, which was markedly attenuated by GSDME deficiency. Oxaliplatin activated caspase-3 and cleaved GSDME, effects that were reversed by the caspase-3 inhibitor Z-DEVD. NFS1 knockdown enhanced GSDME and caspase-3 cleavage, increasing pyroptosis (PI and Annexin-V doublepositive cells) compared to controls. KEGG analysis of RNA sequencing and TCGA data highlighted the MAPK signaling pathway. Western blotting confirmed that oxaliplatin combined with NFS1 knockdown suppressed MAPK pathway proteins.
Discussion: The caspase-3/GSDME axis mediates oxaliplatin-induced GC pyroptosis. High NFS1 expression inhibits GSDME activation, promotes MAPK protein activation, and reduces oxaliplatin sensitivity. These findings suggest that the caspase-3/GSDME pathway offers a novel mechanism for oxaliplatin's antitumor effects. NFS1 may serve as an independent prognostic biomarker in GC, influencing disease progression through MAPK regulation.
Conclusion: NFS1 is a promising therapeutic target for gastric cancer, especially in the study of oxaliplatin-based chemotherapy in combination with a treatment regimen that triggers pyroptosis.
期刊介绍：
Combinatorial Chemistry & High Throughput Screening (CCHTS) publishes full length original research articles and reviews/mini-reviews dealing with various topics related to chemical biology (High Throughput Screening, Combinatorial Chemistry, Chemoinformatics, Laboratory Automation and Compound management) in advancing drug discovery research. Original research articles and reviews in the following areas are of special interest to the readers of this journal:
Target identification and validation
Assay design, development, miniaturization and comparison
High throughput/high content/in silico screening and associated technologies
Label-free detection technologies and applications
Stem cell technologies
Biomarkers
ADMET/PK/PD methodologies and screening
Probe discovery and development, hit to lead optimization
Combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries)
Chemical library design and chemical diversity
Chemo/bio-informatics, data mining
Compound management
Pharmacognosy
Natural Products Research (Chemistry, Biology and Pharmacology of Natural Products)
Natural Product Analytical Studies
Bipharmaceutical studies of Natural products
Drug repurposing
Data management and statistical analysis
Laboratory automation, robotics, microfluidics, signal detection technologies
Current & Future Institutional Research Profile
Technology transfer, legal and licensing issues
Patents.
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