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

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