Isoliquiritigenin induces HMOX1 and GPX4-mediated ferroptosis in gallbladder cancer cells  

作　　者：Zeyu Wang Weijian Li Xue Wang Qin Zhu Liguo Liu Shimei Qiu Lu Zou Ke Liu Guoqiang Li Huijie Miao Yang Yang Chengkai Jiang Yong Liu Rong Shao Xu’an Wang Yingbin Liu 

机构地区：[1]Department of Biliary-Pancreatic Surgery,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [2]State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China [3]Shanghai Research Center of Biliary Tract Disease,Shanghai 200092,China [4]Shanghai Lung Tumor Clinical Medical Center,Shanghai Chest Hospital,Shanghai Jiao Tong University,Shanghai 200030,China [5]Department of General Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University,School of Medicine,Shanghai 200092,China [6]University of Shanghai for Science and Technology,School of Medical Instrument and Food Engineering,Shanghai 200093,China [7]Department of General Surgery,Changzhou Hospital of Traditional Chinese Medicine Nanjing University of Chinese Medicine,Changzhou,Jiangsu 213004,China [8]Department of Pharmacology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Chinese Medical Journal》2023年第18期2210-2220,共11页中华医学杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(Nos.3213000192,81874181,and 31620103910);the Science and Technology Commission of Shanghai Municipality(No.20JC1419101).

摘　　要：Background:Gallbladder cancer(GBC)is the most common malignant tumor of biliary tract.Isoliquiritigenin(ISL)is a natural compound with chalcone structure extracted from the roots of licorice and other plants.Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors.However,the research of ISL against GBC has not been reported,which needs to be further investigated.Methods:The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test,RNA-sequencing,quantitative real-time polymerase chain reaction,reactive oxygen species(ROS)detection,lipid peroxidation detection,ferrous ion detection,glutathione disulphide/glutathione(GSSG/GSH)detection,lentivirus transfection,nude mice tumorigenesis experiment and immunohistochemistry.Results:ISL significantly inhibited the proliferation of GBC cells in vitro.The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC,and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis.Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells.Moreover,ISL significantly reversed the iron content,ROS level,lipid peroxidation level and GSSG/GSH ratio of GBC cells.Finally,ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4.Conclusion:ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and downregulating GPX4 in vitro and in vivo.This evidence may provide a new direction for the treatment of GBC.

关 键 词：ISOLIQUIRITIGENIN Ferroptosis Gallbladder cancer HMOX1 GPX4 

分 类 号：R735.8[医药卫生—肿瘤]