Targeting FASN enhances cisplatin sensitivity via SLC7A11-mediated ferroptosis in cervical cancer

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-04-15 DOI:10.1016/j.tranon.2025.102396

Xiaojun Wang , Qiqiao Du , Qiuwen Mai , Qiaojian Zou , Shuyi Wang , Xiaoying Lin , Qianrun Chen , Mengxun Wei , Chudan Chi , Zhangqing Peng , Karima Abdugheni , Liu Du , Yili Chen , Shuzhong Yao , Junxiu Liu

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Abstract

Objective

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.

Methods

Intracellular levels of reactive oxygen species, glutathione, malondialdehyde and Fe²⁺ were measured as indicators of ferroptosis. Biological information analyses, IC₅₀, 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.

Results

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.

Conclusion

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.

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靶向 FASN 可通过 SLC7A11 介导的宫颈癌铁变态反应增强顺铂敏感性

目的顺铂耐药严重阻碍晚期、复发和转移宫颈癌（CC）患者的治疗前景。我们的研究旨在阐明CC患者顺铂耐药的机制，并为克服CC患者顺铂耐药提供新的治疗策略。方法以细胞内活性氧、谷胱甘肽、丙二醛、铁离子水平作为铁下垂的指标。通过生物信息分析、IC50、免疫荧光、qPCR和western blot分析FASN在CC中的功能，在体内研究TVB-2640与顺铂联用的抗肿瘤作用。结果通过转录组测序和基因表达综合分析（GEO）数据分析，确定脂肪酸合成酶（FASN）是CC顺铂耐药的关键驱动因素。临床安全的FASN抑制剂TVB-2640被发现可以恢复顺铂敏感性，导致异种移植模型中肿瘤生长的协同衰减。在机制上，FASN下调促进铁下垂，降低溶质载体家族7成员11 （SLC7A11）在体外和体内模型中的表达。结论靶向FASN可促进slc7a11介导的铁下垂，提高CC患者顺铂敏感性。TVB-2640联合顺铂在顺铂耐药CC模型中具有较好的协同抗肿瘤作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.