β-Elemene promotes ferroptosis and reverses radioresistance in gastric cancer by inhibiting the OTUB1-GPX4 interaction

Introduction: β-Elemene, derived from Curcuma zedoaria (Wenyujin), is clinically recognized for inducing Apoptosis, inhibiting cell cycle progression, and reversing chemotherapy resistance in various cancers. However, its effects on radioresistant gastric Cancer (GC) remain unclear.

Methods: In this study, radioresistant GC cell lines (MKN45/IR and AGS/IR) were established via multiple low-dose radiations. The impact of β-elemene on radiosensitivity was assessed using CCK-8 and clonogenic assays, with Ferroptosis markers such as ROS, MDA, and Fe²⁺ levels measured. Additionally, the influence of β-elemene on GPX4 and its interaction with OTUB1 was examined through qRT-PCR, Western blot, immunofluorescence, co-immunoprecipitation, and in vivo studies.

Results: Our findings indicate that β-elemene reverses radioresistance in GC cells and significantly inhibits cell growth when combined with radiotherapy. β-Elemene treatment elevated ROS, MDA, and Fe²⁺ levels, enhancing Ferroptosis, which was confirmed by Ferrostatin-1 and Deferoxamine inhibition studies. Mechanistic analysis revealed that β-elemene disrupts the OTUB1-GPX4 interaction, leading to increased GPX4 ubiquitination and degradation, thus promoting Ferroptosis. In vivo studies further demonstrated that β-elemene combined with radiotherapy significantly suppressed tumor growth compared to radiotherapy alone.

Discussion: These results suggest that β-elemene effectively modulates radioresistance in GC by targeting the GPX4 pathway and inducing Ferroptosis. This highlights its potential as a therapeutic adjunct in radiotherapy for resistant GC cases.

GPx4; OUTB1; ferroptosis; gastric cancer; ubiquitination; β-elemene.