Cell Signal. 2026 Oct 9:112912. doi: 10.1016/j.cellsig.2026.112912. Online ahead of print.
ABSTRACT
Mutations of epidermal growth factor receptor (EGFR) closely correlate with differential ferroptosis sensitivity in select cell lines, but the underlying mechanism is poorly understood. In this study, we identified the epidermal growth factor (EGF)-activated EGFR as a correlate of ferroptosis suppression in non-small cell lung carcinoma (NSCLC) cells, an effect linked to increased mitochondrial mass and functional capacity. EGF treatment attenuated ferroptosis induced by ML210, RSL3, or Erastin, whereas CRISPR/Cas9-mediated knockout of EGFR (EGFR) downregulated GCLC/GCLM expression and glutathione (GSH) levels, thereby sensitizing cells to ferroptosis. Across the cell lines tested, sensitivity to ferroptosis inducers varied and could not be attributed solely to EGFR mutation status. In tyrosine kinase inhibitor (TKI)-resistant cells and in post-TKI tumor tissues from NSCLC patients harboring EGFR mutations, we observed downregulation of xCT/SLC7A11 and GCLC/GCLM. Notably, while TKI-resistant cells acquired resistance to the system xc- inhibitor Erastin, they remained sensitive to the GPX4 inhibitor RSL3, suggesting that alternative antioxidant pathways, such as the FSP1/CoQ10 system, may compensate for impaired cystine uptake in the resistant setting. Collectively, our results reveal a correlative link between EGFR signaling, mitochondrial metabolism, and the ROS-NRF2-GCLC/GCLM pathway in modulating ferroptosis in NSCLC cells in a GSH-dependent manner. Furthermore, the sustained vulnerability of TKI-resistant cells to GPX4 inhibition suggests that targeting GPX4 represents a promising therapeutic strategy to overcome TKI resistance, though our findings are hypothesis-generating and require further mechanistic validation.
PMID:42854880 | DOI:10.1016/j.cellsig.2026.112912