Abstract

Aberrant expression of EphA2 (Ephrin receptor A2) in gastric cancer (GC) promotes chemoresistance by suppressing ferroptosis, yet the underlying mechanism remains poorly defined. In this study, we show that EphA2 confers resistance to platinum-based chemotherapy by suppressing ferroptosis through redox homeostasis regulation. Mechanistically, EphA2 directly phosphorylates and activates the deubiquitinase USP38, which in turn stabilizes SLC7A11 by preventing its proteasomal degradation. Elevated SLC7A11 sustains intracellular glutathione homeostasis, attenuates lipid peroxidation, and limits reactive oxygen species accumulation, thereby enabling GC cells to evade ferroptotic cell death under chemotherapeutic stress. Importantly, genetic or pharmacological disruption of the EphA2-USP38 interaction leads to SLC7A11 destabilization, excessive ROS accumulation, ferroptosis induction, and restoration of chemosensitivity. Together, these findings identify the EphA2-USP38/ROS axis as a key determinant of oxaliplatin resistance in GC and highlight a promising therapeutic target for overcoming chemotherapy resistance by reactivating ferroptosis.