{"title":"杉木醇通过tmdd1介导的铁下垂诱导和铁硫簇抑制优先抑制转移性肺腺癌。","authors":"Yanbin Kuang, Suyang Yang, Xiaoting Tian, Huiyan Cheng, Beibei Liu, Congcong Zhang, Baohui Han, Wei Zhang, Xiao Zhang, Yuqing Lou","doi":"10.1016/j.canlet.2025.218046","DOIUrl":null,"url":null,"abstract":"<p><p>Dysregulated ISC metabolism has been implicated in cancer progression, but its role in LUAD pathogenesis and therapeutic targeting remains poorly understood. Here, we demonstrate that ISC biogenesis is significantly upregulated in LUAD, driven by transcription factors KLF15 and ZNF384, which activate GLRX5, LYRM4, NFS1 and BOLA3 promoters. IL-1β promotes PCAF mitochondrial translocation, releasing EP300 to amplify KLF15/ZNF384-mediated transcriptional activation. The natural monoterpenoid Hinokitiol inhibits LUAD growth by disrupting EP300-KLF15/ZNF384 interactions, suppressing ISC biogenesis gene expression and inducing ferroptosis. Mechanistically, the membrane protein TMDD1, particularly its cytoplasmic domain, promotes Hinokitiol's anti-tumor effects by facilitating EP300-KLF15/ZNF384 dissociation and inhibiting ISC biogenesis. Remarkably, Hinokitiol exhibits stage-dependent efficacy, with superior suppression of metastatic (stage IV) tumors linked to heightened ferroptosis sensitivity. This study not only elucidates the transcriptional machinery governing ISC biogenesis in LUAD but also highlights Hinokitiol's dual mechanism as a promising stage-specific therapeutic agent, offering novel strategies for advanced disease management.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218046"},"PeriodicalIF":10.1000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hinokitiol preferentially suppresses metastatic lung adenocarcinoma via TMDD1-mediated ferroptosis induction and iron-sulfur cluster inhibition.\",\"authors\":\"Yanbin Kuang, Suyang Yang, Xiaoting Tian, Huiyan Cheng, Beibei Liu, Congcong Zhang, Baohui Han, Wei Zhang, Xiao Zhang, Yuqing Lou\",\"doi\":\"10.1016/j.canlet.2025.218046\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Dysregulated ISC metabolism has been implicated in cancer progression, but its role in LUAD pathogenesis and therapeutic targeting remains poorly understood. Here, we demonstrate that ISC biogenesis is significantly upregulated in LUAD, driven by transcription factors KLF15 and ZNF384, which activate GLRX5, LYRM4, NFS1 and BOLA3 promoters. IL-1β promotes PCAF mitochondrial translocation, releasing EP300 to amplify KLF15/ZNF384-mediated transcriptional activation. The natural monoterpenoid Hinokitiol inhibits LUAD growth by disrupting EP300-KLF15/ZNF384 interactions, suppressing ISC biogenesis gene expression and inducing ferroptosis. Mechanistically, the membrane protein TMDD1, particularly its cytoplasmic domain, promotes Hinokitiol's anti-tumor effects by facilitating EP300-KLF15/ZNF384 dissociation and inhibiting ISC biogenesis. Remarkably, Hinokitiol exhibits stage-dependent efficacy, with superior suppression of metastatic (stage IV) tumors linked to heightened ferroptosis sensitivity. This study not only elucidates the transcriptional machinery governing ISC biogenesis in LUAD but also highlights Hinokitiol's dual mechanism as a promising stage-specific therapeutic agent, offering novel strategies for advanced disease management.</p>\",\"PeriodicalId\":9506,\"journal\":{\"name\":\"Cancer letters\",\"volume\":\" \",\"pages\":\"218046\"},\"PeriodicalIF\":10.1000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.canlet.2025.218046\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.canlet.2025.218046","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Hinokitiol preferentially suppresses metastatic lung adenocarcinoma via TMDD1-mediated ferroptosis induction and iron-sulfur cluster inhibition.
Dysregulated ISC metabolism has been implicated in cancer progression, but its role in LUAD pathogenesis and therapeutic targeting remains poorly understood. Here, we demonstrate that ISC biogenesis is significantly upregulated in LUAD, driven by transcription factors KLF15 and ZNF384, which activate GLRX5, LYRM4, NFS1 and BOLA3 promoters. IL-1β promotes PCAF mitochondrial translocation, releasing EP300 to amplify KLF15/ZNF384-mediated transcriptional activation. The natural monoterpenoid Hinokitiol inhibits LUAD growth by disrupting EP300-KLF15/ZNF384 interactions, suppressing ISC biogenesis gene expression and inducing ferroptosis. Mechanistically, the membrane protein TMDD1, particularly its cytoplasmic domain, promotes Hinokitiol's anti-tumor effects by facilitating EP300-KLF15/ZNF384 dissociation and inhibiting ISC biogenesis. Remarkably, Hinokitiol exhibits stage-dependent efficacy, with superior suppression of metastatic (stage IV) tumors linked to heightened ferroptosis sensitivity. This study not only elucidates the transcriptional machinery governing ISC biogenesis in LUAD but also highlights Hinokitiol's dual mechanism as a promising stage-specific therapeutic agent, offering novel strategies for advanced disease management.
期刊介绍:
Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research.
Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy.
By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.