胃癌增殖和死亡机制失衡是其恶性生物学特征的重要基础。作为受内外信号严密调控的新型细胞死亡方式，铁死亡在胃癌中的作用值得广泛关注。脂氧合酶（ALOX）感受外界微环境信号并介导胞内铁依赖脂过氧化物积累，促进细胞铁死亡。我们预实验发现：胃癌患者组织中ALOX15表达量与铁死亡水平明显降低；且与血清中显著增高的外泌体miR-522呈负相关。进一步发现胃癌微环境成纤维细胞去泛素化酶USP7升高，可促进miRNA分拣蛋白hnRNPA1表达和miR-522大量外泌；而miR-522可靶向ALOX15。据此我们推测：胃癌相关成纤维细胞可通过USP7调控外泌体miR-522释放，靶向胃癌ALOX15，降低脂过氧化物与铁离子水平，抑制胃癌铁死亡发生。本课题拟从临床、体内和体外实验揭示胃癌铁死亡发生和调控的新机制；并尝试靶向成纤维细胞外泌体miR-522，增加胃癌铁死亡、减轻耐药，为胃癌治疗提供新靶点和策略。

The imbalance between proliferation and death in gastric cancer is the important basis that leads to its malignant biological characteristics. As a novel type of cell death tightly regulated by internal and external signals, the role of Ferroptosis in gastric cancer deserves wide attention. Arachidonate-lipoxygenase (ALOX) can sense the signals from external microenvironment and mediate the intracellular iron-dependent lipid peroxide accumulation, thus promoting Ferroptosis. According to our preliminary experiments, the ALOX15 expression, as well as the levels of Ferroptosis was sharply decreased in gastric tumor tissues, and showed negative relationship with the up-regulated exosome miR-522. Further study illustrated that the deubiquitination enzyme USP7 is elevated in the fibroblasts of gastric tumor environment, resulting in the enhanced expression of miRNA-sorting protein hnRNPA1 and the massive secretion of miR-522. And miR-522 was proved to directly target ALOX15. Thus we propose that USP7 promotes miR-522 secretion from gastric cancer-associated fibroblasts, and suppresses ALOX15 expression in gastric cancer cells, reducing the levels of lipoid peroxide and iron ions, and eventually leads to inhibited Ferroptosis. This project is designed to reveal the new mechanism of occurrence and regulation of Ferroptosis in gastric cancer. And we will also try to boost the levels of Ferroptosis and altering drug resistance in gastric cancer, providing novel targets and strategy for the gastric cancer treatment.