Abstract

Solid tumors such as gastric cancers exploit hypoxia-induced adaptive mechanisms to evade cell death. Here, we identify a hypoxia-triggered signaling axis in which the spliced form of XBP1s transcriptionally activates MYDGF. We demonstrate that MYDGF competitively binds the ubiquitin adaptor protein UBQLN1 at the STI1-4 domain, thereby blocking UBQLN1-mediated recognition and endoplasmic reticulum-associated degradation (ERAD) of LCN2. Stabilized LCN2 sequesters redox-active iron and inhibits iron-dependent lipid peroxidation, thereby suppressing ferroptosis. Hypoxia promotes the splicing of XBP1s, which directly binds to the MYDGF promoter, increasing its expression. Genetic disruption of this axis sensitizes gastric cancer cells to ferroptosis inducers both in vitro and in vivo. These findings reveal a previously unrecognized mechanism of hypoxia-induced ferroptosis resistance and suggest that the XBP1–MYDGF–UBQLN1–LCN2 pathway is a therapeutic target for hypoxic tumors.