Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-05-22 DOI:10.1016/j.redox.2025.103693

Jingwen Chen , Yedi Huang , Daocheng Zuo , Ruimin Shan , Songmao Li , Ran Li , Dong Hua , Qiang Zhan , Xudong Song , Yun Chen , Pei Ma , Ling Ma , Guoquan Tao , Yongqian Shu

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引用次数: 0

Abstract

Aims

This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells.

Methods

We constructed FGFR-TKI-resistant cell lines from GC cells. RNA sequencing was performed to identify differentially expressed genes (DEGs) related to ferroptosis and assess lipid metabolism in resistant cells. GC microenvironment lipid profile was characterized by HPLC-MS/MS lipidomics. The effects of CHAC1 and cholesterol synthesis modulation on ferroptosis and FGFR-TKI resistance were assessed using in vitro and in vivo models.

Results

We found that FGFR-TKI can induce ferroptosis in FGFR-TKI-sensitive cells, while resistant cells exhibit decreased sensitivity to ferroptosis due to reduced CHAC1 expression, a key glutathione-specific degrading enzyme. Overexpression of CHAC1 enhances FGFR-TKI cytotoxicity. Additionally, cholesterol accumulation in resistant cells, associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced ferroptosis resistance. In vivo studies show that CHAC1 overexpression or cholesterol synthesis inhibition can reverse FGFR-TKI resistance, which is dependent on ferroptosis.

Conclusions

Dysregulated lipid homeostasis downregulated CHAC1-mediated ferroptosis, leading to FGFR-TKI resistance in gastric cancer. Overexpression of CHAC1 or inhibiting cholesterol synthesis presents promising therapeutic strategies to overcome FGFR-TKI resistance in GC.

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胃癌中脂质稳态失调破坏chac1介导的铁下垂驱动成纤维细胞生长因子受体酪氨酸激酶抑制剂AZD4547耐药

目的探讨胃癌（GC）对FGFR酪氨酸激酶抑制剂（FGFR- tki）获得性耐药的机制，重点研究肿瘤细胞脂质代谢与铁凋亡之间的相互作用。方法利用GC细胞构建抗fgfr - tki细胞系。通过RNA测序鉴定与铁下垂相关的差异表达基因（DEGs），并评估耐药细胞的脂质代谢。采用HPLC-MS/MS脂质组学对GC微环境脂质谱进行表征。通过体外和体内模型评估CHAC1和胆固醇合成调节对铁下沉和FGFR-TKI耐药性的影响。结果我们发现FGFR-TKI可以诱导FGFR-TKI敏感细胞的铁死亡，而耐药细胞对铁死亡的敏感性降低是由于CHAC1（一种关键的谷胱甘肽特异性降解酶）的表达减少。CHAC1过表达增强FGFR-TKI的细胞毒性。此外，抵抗细胞中的胆固醇积累与硬脂酸（SA）摄取减少相关，赋予fgfr - tki诱导的铁凋亡抵抗。体内研究表明，CHAC1过表达或胆固醇合成抑制可逆转FGFR-TKI耐药，这种耐药依赖于铁下垂。结论脂质稳态失调下调chac1介导的铁下垂，导致胃癌FGFR-TKI耐药。CHAC1过表达或抑制胆固醇合成是克服GC中FGFR-TKI耐药的有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.