Core Viewpoint - Ferroptosis is a newly discovered iron-dependent form of programmed cell death that plays a significant role in the development of various diseases, including cancer [2][4]. Group 1: Mechanism of Ferroptosis - Reactive oxygen species (ROS) are crucial in initiating lipid peroxidation and ferroptosis, significantly affecting chemotherapy resistance in cancer [3][10]. - The study published in Nature Cell Biology reveals that O-GlcNAc transferase (OGT) acts as a ROS sensor in hepatocellular carcinoma (HCC) [4][10]. - ROS-induced oxidation activates OGT, which then modifies the transcription factor FOXK2, promoting its nuclear translocation and upregulating the expression of the key gene SLC7A11, thereby inhibiting ferroptosis and enhancing chemotherapy resistance in liver cancer cells [4][8]. Group 2: Implications for Cancer Treatment - The research elucidates a ROS-mediated oxidation-O-GlcNAcylation cascade that integrates ROS signaling, O-GlcNAc modification, and FOXK2-mediated transcriptional regulation of SLC7A11, contributing to resistance against ferroptosis and chemotherapy [10]. - Targeting this mechanism may provide a novel approach to reactivate ferroptosis, offering new strategies to overcome cancer resistance [10].