Wang Xiaojun, Du Qiqiao, Mai Qiuwen, Zou Qiaojian, Wang Shuyi, Lin Xiaoying, Chen Qianrun, Wei Mengxun, Chi Chudan, Peng Zhangqing, Abdugheni Karima, Du Liu, Chen Yili, Yao Shuzhong, Liu Junxiu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou City, Guangdong Province, PR China; Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou City, Guangdong Province, PR China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou City, Guangdong Province, PR China; Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou City, Guangdong Province, PR China.
Transl Oncol. 2025 Jun;56:102396. doi: 10.1016/j.tranon.2025.102396. Epub 2025 Apr 15.
The cisplatin resistance significantly hinders the prospects for curing patients with advanced, recurrent, and metastatic cervical cancer (CC). Our study aims to clarify the mechanisms underlying cisplatin resistance in CC and provide a novel treatment strategy to overcome the cisplatin resistance of CC patients.
Intracellular levels of reactive oxygen species, glutathione, malondialdehyde and Fe were measured as indicators of ferroptosis. Biological information analyses, IC, immunofluorescence assays, qPCR and western blot analyses were conducted to elucidate the functions of FASN in CC. In vivo studies were conducted to examine the antitumor effects of the combination of TVB-2640 and cisplatin.
Fatty acid synthase (FASN) was identified as a key driver of cisplatin resistance in CC through transcriptome sequencing and Gene Expression Omnibus (GEO) data analysis. The clinically safe FASN inhibitor TVB-2640 was found to restore cisplatin sensitivity, resulting in synergistic tumor growth attenuation in xenograft models. Mechanistically, FASN downregulation promoted ferroptosis and reduced solute carrier family 7 member 11 (SLC7A11) expression, both in vitro and in vivo models.
Targeting FASN enhances cisplatin sensitivity in CC by promoting SLC7A11-mediated ferroptosis. TVB-2640 combined with cisplatin had superior synergistic antitumor effects in cisplatin-resistant CC models.
顺铂耐药显著阻碍了晚期、复发和转移性宫颈癌（CC）患者的治愈前景。本研究旨在阐明CC中顺铂耐药的潜在机制，并提供一种新的治疗策略来克服CC患者的顺铂耐药性。
检测细胞内活性氧、谷胱甘肽、丙二醛和铁的水平作为铁死亡的指标。进行生物信息分析、IC、免疫荧光分析、qPCR和蛋白质印迹分析以阐明FASN在CC中的功能。进行体内研究以考察TVB-2640与顺铂联合使用的抗肿瘤作用。
通过转录组测序和基因表达综合数据库（GEO）数据分析，脂肪酸合酶（FASN）被确定为CC中顺铂耐药的关键驱动因素。发现临床安全的FASN抑制剂TVB-2640可恢复顺铂敏感性，导致异种移植模型中肿瘤生长协同减弱。机制上，在体外和体内模型中，FASN下调均促进铁死亡并降低溶质载体家族7成员11（SLC7A11）的表达。
靶向FASN通过促进SLC7A11介导的铁死亡增强CC对顺铂的敏感性。在顺铂耐药的CC模型中，TVB-2640与顺铂联合具有卓越的协同抗肿瘤作用。
