Celastrol Induces Ferroptosis by Regulating CERKL to Exert Anti-Gastric Cancer Effect.

Abstract

Gastric cancer is a significant global health issue. Celastrol, a natural compound, has shown antitumor potential, but its molecular mechanism in gastric cancer remains unclear. In this study, we treated HGC-27 cells with celastrol and employed CCK8, colony formation, and Transwell assays, revealing its inhibitory effect on cell proliferation and migration. Flow cytometry assay results showed that celastrol could elevate the level of reactive oxygen species (ROS) in HGC-27 cells. By using the iron ion and malondialdehyde (MDA) detection kits, it was found that celastrol promoted the accumulation of iron ions (Fe[Formula: see text] in HGC-27 cells, increased the MDA content, and simultaneously decreased the glutathione (GSH) content. Additionally, Western blot analysis indicated that celastrol exerts an inhibitory effect on the expression of ferroptosis-marker proteins GPX4 and SLC7A11. PCR array and further experiments identified CERKL as a key factor, whose downregulation by celastrol was associated with enhanced ferroptosis. In vivo, celastrol inhibited tumor growth without affecting body weight or organ histology. Our findings suggest that celastrol may inhibit gastric cancer via CERKL-regulated ferroptosis, providing a potential therapeutic strategy.