Xu Kang, Chen Hao, Zhu Xingyu, Li Han, Liu Xinyu, Sang Yaodong, Wang Xiaohan, Cui Xiaoling, Cai Baoshan, Shang Liang, Chong Wei, Li Leping
Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong First Medical University, Jinan, 250021, China.
Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, Jinan, 250021, China.
J Exp Clin Cancer Res. 2025 Jun 18;44(1):176. doi: 10.1186/s13046-025-03435-2.
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.
弥漫型胃癌（DGC）约占胃癌病例的三分之一，但与肠型胃癌（IGC）相比，其在临床上侵袭性更强，生存预后更差。我们的研究显示，与IGC患者相比，DGC患者中ESRP1表达显著降低，其高表达与DGC患者预后呈正相关。体外和体内实验模型均表明，ESRP1具有抑制DGC恶性进展的能力。机制上，ESRP1与促进铁死亡的调节因子DHCR7相互作用，从而上调DHCR7表达并增强DGC细胞对铁死亡的易感性。在ESRP1高表达的DGC患者中，诱导铁死亡疗法成为一种有前景的治疗选择。此外，对于ESRP1低表达的DGC病例，我们鉴定出了几种有效的小分子药物。这些发现共同将ESRP1定位为DGC干预的潜在治疗靶点。
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