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

• DOI: 10.1016/j.redox.2025.103693
• Publication Date: 2025-05-22T06:55:33Z
• Authors: 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
• Keywords: Homeostasis

This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on interplay between ferroptosis and lipid metabolism of tumor cells. We constructed FGFR-TKI-resistant cell lines from GC RNA sequencing was performed identify differentially expressed genes (DEGs) related assess resistant microenvironment profile characterized by HPLC-MS/MS lipidomics. The effects CHAC1 cholesterol synthesis modulation FGFR-TKI were assessed using vitro vivo models. found that can induce FGFR-TKI-sensitive cells, while cells exhibit decreased sensitivity due reduced expression, a key glutathione-specific degrading enzyme. Overexpression enhances cytotoxicity. Additionally, accumulation associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced resistance. In studies show overexpression or inhibition reverse resistance, which is dependent ferroptosis. Dysregulated homeostasis downregulated CHAC1-mediated ferroptosis, leading cancer. inhibiting presents promising therapeutic strategies overcome GC.