Hinokitiol preferentially suppresses metastatic lung adenocarcinoma via TMDD1-mediated ferroptosis induction and iron-sulfur cluster inhibition.

IF 10.1 1区 医学 Q1 ONCOLOGY
Yanbin Kuang, Suyang Yang, Xiaoting Tian, Huiyan Cheng, Beibei Liu, Congcong Zhang, Baohui Han, Wei Zhang, Xiao Zhang, Yuqing Lou
{"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}
引用次数: 0

Abstract

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.

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。
ISC代谢失调与癌症进展有关,但其在LUAD发病机制和治疗靶向中的作用仍知之甚少。本研究表明,在转录因子KLF15和ZNF384的驱动下,LUAD中的ISC生物发生显著上调,这两个转录因子激活GLRX5、LYRM4、NFS1和BOLA3启动子。IL-1β促进PCAF线粒体易位,释放EP300以放大KLF15/ znf384介导的转录激活。天然单萜扁柏醇通过破坏EP300-KLF15/ZNF384相互作用、抑制ISC生物发生基因表达和诱导铁下垂来抑制LUAD生长。机制上,膜蛋白TMDD1,特别是其胞质结构域,通过促进EP300-KLF15/ZNF384的解离和抑制ISC的生物发生,促进了桧木醇的抗肿瘤作用。值得注意的是,扁柏醇表现出分期依赖的疗效,对转移性(IV期)肿瘤的抑制优于与铁下垂敏感性增高相关的转移性肿瘤。本研究不仅阐明了LUAD中控制ISC生物发生的转录机制,而且强调了扁柏醇作为一种有前景的阶段特异性治疗药物的双重机制,为晚期疾病管理提供了新的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信