Abstract 3078: Targeting a ROS-induced oxidation and O-GlcNAcylation cascade to overcome drug resistance across multiple cancer types

Abstract Reactive oxygen species (ROS) are critical in lipid peroxidation and the initiation of ferroptosis, which significantly impacts chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified that O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, acts as a sensor for ROS induced by ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates OGT. Once activated, OGT O-GlcNAcylates FOXK2, which enhances its interaction with importin α, promoting its nuclear translocation and subsequent transcription of SLC7A11, thereby inhibiting ferroptosis. Moreover, ferroptosis-induced activation of the ATM-CHK2 pathway and subsequent phosphorylation of FOXK2 further boost FOXK2 O-GlcNAcylation and SLC7A11 transcription. Clinically, the elevated OGT-FOXK2-SLC7A11 axis drives tumorigenesis and promotes resistance to chemoradiotherapy across various cancer types, including hepatocellular carcinoma (HCC). Our study uncovers a ROS-induced oxidation-O-GlcNAcylation cascade specific to ferroptosis, which integrates ROS signaling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription, and chemoradiotherapy resistance. Targeting this cascade represents a promising approach to overcoming drug resistance in multiple cancer types. Citation Format: Juanjuan Li, Huadong Pei, Feng Yao, Hemeng Zhang, Junfeng Ma. Targeting a ROS-induced oxidation and O-GlcNAcylation cascade to overcome drug resistance across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3078.