WTX-L/β-arrestin2/LCN2 axis controls vulnerability to ferroptosis in gastric cancer

• DOI: 10.1016/j.isci.2025.111964
• Publication Date: 2025-02-07T16:38:53Z
• Authors: Yangwei Xu; Xuexia Qian; Guixing Cai; Zhihao Lin; Weiye Huang; Chuangyuan Wang; Hongmei Wu; Yiqiong Zhang; Jingbo Sun; Qingling Zhang
• Keywords: Vulnerability

Gastric cancer (GC) is one of the most prevalent and lethal cancers worldwide. Ferroptosis a form iron-dependent regulated cell death emerging as promising strategy for therapy, whereas regulation mechanism remains unclear. WTX has been recognized potential tumor suppressor, but attempts at targeted therapy have not achieved substantial progress. Further research into structure, function, mechanisms urgently needed. Herein, we identified long isoform (WTX-L) potent ferroptosis effector in GC. Mechanistically, WTX-L competitively interacts with β-arrestin2, disrupting its direct binding to IκBα subsequently activating NF-κB/LCN2 pathway. LCN2 further triggers by significantly increasing labile Fe2+ pool promoting excessive lipid peroxidation. Blockade WTX-L/β-arrestin2/NF-κB/LCN2 axis diminished activity inducers (erastin RSL3) vivo. Collectively, these findings reveal that targeting vulnerabilities through may represent