ESRP1 exerts anti-tumor role by promoting ferroptosis in diffuse-type gastric cancer.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer cases, but it is clinically more aggressive and associated with poorer survival prognosis compared to intestinal-type gastric cancer (IGC). Our study revealed significantly reduced ESRP1 expression in DGC patients relative to IGC counterparts, with its high expression positively correlating with DGC patient prognosis. Both in vitro and in vivo experimental models demonstrated that ESRP1 has the ability to hinder the malignant progression of DGC. Mechanistically, ESRP1 interacts with DHCR7, a ferroptosis-promoting regulator, thereby upregulating DHCR7 expression and enhancing ferroptosis susceptibility in DGC cells. In DGC patients with high ESRP1 expression, ferroptosis-inducing therapy emerges as a promising treatment alternative. Moreover, for ESRP1-low DGC cases, we identified several potent small-molecule drugs. These findings collectively position ESRP1 as a potential therapeutic target for DGC intervention.