WTX-L/B-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 novel form of iron-dependent regulated cell death emerging as a promising strategy for cancer therapy, whereas the upstream regulation mechanism remains not fully clear. WTX has been widely recognized as a potential tumor suppressor, but attempts at targeted therapy have yet to achieve substantial progress. Further research into the structure, function, and mechanisms of WTX is urgently needed. In this study, we identified a long isoform of WTX (WTX-L) as a potent ferroptosis effector in the progression of GC through in vitro and in vivo experiments combined with transcriptomic and proteomic analyses. Mechanistically, WTX-L localizes to the plasma membrane and competitively interacts with B-arrestin2, disrupting its direct binding to IKBa, which is essential for the activation of the NF-KB pathway. Consequently, the NF-KB pathway is activated, leading to the upregulation of LCN2, a downstream target gene of NF-KB. The upregulation of LCN2 subsequently triggers ferroptosis by significantly increasing the labile free iron pool and promoting excessive lipid peroxidation. Genetic blockade of the WTX-L/B-arrestin2/NF-KB/LCN2 axis significantly diminished the activity of ferroptosis inducers (erastin and RSL3) in orthotopic GC mouse models. Collectively, these findings reveal a previously unappreciated function of WTX-L in ferroptosis and suggest that targeting the vulnerabilities associated with ferroptosis may represent an innovative therapeutic strategy for GC.