Recently, a significant study by Prof. Han Suxia’s team from the Department of Radiation Oncology at the First Affiliated Hospital of Xi’an Jiaotong University was published in Nature Cell Biology, uncovering a new mechanism by which liver cancer cells develop resistance to chemoradiotherapy.
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a crucial role in tumor progression and treatment sensitivity. Although ROS is known to contribute to lipid peroxidation and ferroptosis, how cancer cells sense ROS and counteract therapy-induced cell death (including ferroptosis) remains unclear.
ROS Activates OGT Enzyme: The study found that ROS oxidizes the Cys845 residue in OGT, increasing its enzymatic activity and enhancing O-GlcNAc modification, which helps cancer cells evade ferroptosis.
OGT-SLC7A11 Signaling Axis: OGT promotes SLC7A11 transcription, boosting cystine uptake and suppressing ferroptosis, leading to chemoradiotherapy resistance in liver cancer.
Therapeutic Potential: Targeting OGT or this signaling pathway may restore ferroptosis sensitivity, offering a new strategy to overcome treatment resistance.
This research is the first to elucidate the role of the ROS-OGT-FOXK2-SLC7A11 axis in liver cancer chemoradiotherapy resistance, providing a promising therapeutic target. Future drug development targeting this pathway could improve treatment outcomes for liver cancer patients.