{"title":"ACSL1缺失促进透明细胞肾癌的铁下垂抵抗。","authors":"Shangguo Wang, Yuxiong Wang, Bin Liu, Dan Zhang, Zehua Zhang, Hongxia Yang, Guangtao Li, Xiaodong Zhao, Jiaxin Liu, Qianhui Li, Yifan Song, Yanghe Zhang, Yishu Wang, Honglan Zhou","doi":"10.1080/15384047.2025.2567815","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.</p><p><strong>Methods: </strong>Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.</p><p><strong>Results: </strong>ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.</p><p><strong>Conclusion: </strong>ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"26 1","pages":"2567815"},"PeriodicalIF":4.6000,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505508/pdf/","citationCount":"0","resultStr":"{\"title\":\"Loss of ACSL1 fuels ferroptosis resistance in clear cell renal carcinoma.\",\"authors\":\"Shangguo Wang, Yuxiong Wang, Bin Liu, Dan Zhang, Zehua Zhang, Hongxia Yang, Guangtao Li, Xiaodong Zhao, Jiaxin Liu, Qianhui Li, Yifan Song, Yanghe Zhang, Yishu Wang, Honglan Zhou\",\"doi\":\"10.1080/15384047.2025.2567815\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.</p><p><strong>Methods: </strong>Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.</p><p><strong>Results: </strong>ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.</p><p><strong>Conclusion: </strong>ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.</p>\",\"PeriodicalId\":9536,\"journal\":{\"name\":\"Cancer Biology & Therapy\",\"volume\":\"26 1\",\"pages\":\"2567815\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-12-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505508/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Biology & Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/15384047.2025.2567815\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/10/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2025.2567815","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/10/6 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
Loss of ACSL1 fuels ferroptosis resistance in clear cell renal carcinoma.
Background: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.
Methods: Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.
Results: ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.
Conclusion: ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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