Exosomal SLC1A5 from Senescent Endothelial Cells Promotes Gastric Cancer Progression by Dampening Ferroptosis via the EGFR/SRC/YAP1/GPX4 Signaling

A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.