Suppressing the OTUD7A/KDM5B/GABPA axis enhances the sensitivity of cisplatin through inducing ferroptosis in KRAS-mutant LUAD

KRAS-mutant lung adenocarcinoma (LUAD), due to its evolution of more complex antioxidant metabolic mechanisms, exhibits poorer sensitivity to conventional platinum-based drugs compared to other types of LUAD. Ferroptosis, as a means of inducing cell death in cancer therapy, shows unique features and potential therapeutic effects compared to the conventional form of apoptosis, which is frequently obstructed by drug resistance. In human KRAS-mutant LUAD cell lines and mouse models, we found that the deubiquitinase OTU deubiquitinase 7A (OTUD7A) precisely regulates the lysine demethylase 5B (KDM5B). Inhibition of KDM5B expression increases the H4K20me3 level, which in turn downregulates the expression of transcription factor GABPA associated with mitochondrial function, ultimately promoting the production of more Reactive Oxygen Species (ROS) by mitochondria and inducing ferroptosis. Additionally, in in vivo organoid models, cisplatin (CDDP) induced ferroptosis combined with GABPA inhibition demonstrated superior anticancer effects compared to conventional platinum-based drugs. This research identifies new targets and regulatory networks that hold promise for developing ferroptosis-based therapies for KRAS-mutant LUAD.