Scientists Discover New Target for Liver Cancer Resistance to Chemoradiotherapy: ROS-OGT-FOXK2-SLC7A11 Signaling Axis

                            Scientists Discover New Target for Liver Cancer Resistance to Chemoradiotherapy: ROS-OGT-FOXK2-SLC7A11 Signaling Axis

Abstract

A groundbreaking study led by Prof. Han Suxia’s team from the First Affiliated Hospital of Xi’an Jiaotong University has been published in Nature Cell Biology, revealing a key mechanism by which liver cancer cells resist chemoradiotherapy through the ROS-OGT-FOXK2-SLC7A11 signaling axis. The research demonstrates that reactive oxygen species (ROS) oxidize a critical site (Cys845) in the OGT enzyme, enhancing its activity and subsequently upregulating SLC7A11 expression to inhibit ferroptosis, thereby promoting treatment resistance. This discovery provides a novel therapeutic target for overcoming liver cancer chemoradiotherapy resistance.

Source

Nature Cell Biology, First Affiliated Hospital of Xi’an Jiaotong University

Content

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.

Background

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.

Key Findings

1. 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.

2. OGT-SLC7A11 Signaling Axis: OGT promotes SLC7A11 transcription, boosting cystine uptake and suppressing ferroptosis, leading to chemoradiotherapy resistance in liver cancer.

3. Therapeutic Potential: Targeting OGT or this signaling pathway may restore ferroptosis sensitivity, offering a new strategy to overcome treatment resistance.

Significance

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.