Brusatol induces ferroptosis to inhibit hepatocellular carcinoma progression by targeting ATF3

作者全名：Wan, Yuanyuan; Cheng, Jingsong; Gan, Debiao; He, Jiaming; Chen, An; Ma, Jing; Li, Yunying; Wang, Xiao; Ran, Jianhua; Chen, Dilong; Li, Jing

作者地址：[Wan, Yuanyuan; Cheng, Jingsong; He, Jiaming; Chen, An; Ma, Jing; Li, Yunying; Li, Jing] Chongqing Med Univ, Dept Histol & Embryol, Coll Basic Med, Lab Stem Cells & Tissue Engn, Chongqing 400016, Peoples R China; [Cheng, Jingsong] Chongqing Med Univ, Clin Coll 2, Chongqing, Peoples R China; [Gan, Debiao] Chengde Med Univ, Chengde, Peoples R China; [Wang, Xiao] Chongqing Med Univ, Lab Teaching & Management Ctr, Chongqing, Peoples R China; [Ran, Jianhua] Chongqing Med Univ, Coll Basic Med, Neurosci Res Ctr, Chongqing, Peoples R China; [Chen, Dilong] Chongqing Three Gorges Med Coll, Chongqing Key Lab Dev & Utilizat Genuine Med Mat, Fac Basic Med Sci, Wanzhou 404100, Peoples R China; [Chen, Dilong] Chongqing Inst Food & Drug Control, NMPA Key Lab Qual Monitoring Narcot Drugs & Psych, Chongqing, Peoples R China

通信作者：Li, J (通讯作者)，Chongqing Med Univ, Dept Histol & Embryol, Coll Basic Med, Lab Stem Cells & Tissue Engn, Chongqing 400016, Peoples R China.; Chen, DL (通讯作者)，Chongqing Three Gorges Med Coll, Chongqing Key Lab Dev & Utilizat Genuine Med Mat, Fac Basic Med Sci, Wanzhou 404100, Peoples R China.

来源：CHEMICAL BIOLOGY & DRUG DESIGN

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001243492800001

JCR分区：Q2

影响因子：3.2

年份：2024

卷号：103

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：ATF3; bioinformatics; brusatol; ferroptosis; hepatocellular carcinoma

摘要：Ferroptosis is a novel form of programmed cell death that is triggered by iron-dependent lipid peroxidation. Brusatol (BRU), a natural nuclear factor erythroid 2-related factor 2 inhibitor, exhibits potent anticancer effects in various types of cancer. However, the exact mechanism of BRU in the treatment of hepatocellular carcinoma (HCC) remains unknown. The anticancer effects of BRU in HCC were detected using cell counting kit-8 and colony formation assays and a xenograft model. RNA sequencing (RNA-seq) and bioinformatics analyses of HCC cells were utilized to elucidate the mechanism underlying the effects of BRU in HCC. The levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2+ were measured using assay kits. The expression of activating transcription factor 3 (ATF3) was tested using RT-qPCR, western blotting, and immunofluorescence staining. The role of ATF3 in BRU-induced ferroptosis was examined using siATF3. BRU significantly inhibited HCC cell proliferation, both in vitro and in vivo. BRU activated the ferroptosis signaling pathway and increased ATF3 expression. Furthermore, ATF3 knockdown impeded BRU-induced ferroptosis. BRU suppressed HCC growth through ATF3-mediated ferroptosis, supporting BRU as a promising therapeutic agent for HCC. In this study, we explored the mechanism of action of brusatol in hepatocellular carcinoma. Using RNA-seq and through in vitro and in vivo studies, we determined that brusatol suppresses hepatocellular carcinoma progression by inducing ATF3-mediated ferroptosis. Therefore, our research revealed the biological effect of brusatol treatment and provided ATF3 as a novel therapeutic target and prognostic biomarker for HCC therapy.image

基金机构：Science and Technology Research Program of Chongqing Municipal Education Commission; Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, College of Basic Medicine, Chongqing Medical University

基金资助正文：We are deeply grateful for the invaluable support provided by the Laboratory of Stem Cell and Tissue Engineering, Department of Histology and Embryology, College of Basic Medicine, Chongqing Medical University.