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

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 exhi

SUBMITTER: Chen J 

PROVIDER: S-EPMC12167034 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature