铁死亡是一种铁依赖的、以谷胱甘肽过氧化物酶4活性丧失、脂质过氧化物沉积为特点的程序性细胞死亡新形式。诱导铁死亡成为近年来探索肿瘤治疗新策略的研究热点。目前，胰腺癌中铁死亡机制研究罕有报道。据此，本课题拟通过探讨SMAD4缺失突变胰腺癌细胞自噬与铁死亡之间关系，深入解析调控SMAD4表达缺失胰腺癌铁死亡的内在分子机制。我们前期研究发现，相较于SMAD4野生型胰腺癌细胞，SMAD4缺失突变胰腺癌细胞对erastin诱导的铁死亡更为敏感。深入研究发现，GPX1通过影响SMAD4缺失突变胰腺癌细胞自噬水平，进而调控p62-Keap1-NRF2通路诱导铁死亡，由此提出“GPX1-p62-Keap1-NRF2”这一全新功能轴。我们拟进一步开展体内外和临床样本的验证及干预研究，明确这一新分子机制在SMAD4缺失突变胰腺癌自噬及铁死亡中的作用，为临床上改善胰腺癌的不良预后及探索个体化治疗提供潜在的靶点。

Ferroptosis is a new form of programmed cell death, which is mainly characterized by iron-dependent, the loss of glutathione peroxidase 4 activity and lipid peroxide deposition. The research of inducing ferroptosis has become a hotspot in exploring new strategies of tumor treatment in recent years. At present, the mechanism of ferroptosis in pancreatic cancer is rarely reported. Therefore, this study aims to explore the regulatory relationship between autophagy and ferroptosis of SMAD4 deletion mutation pancreatic cancer cells, and to further analyze the internal molecular mechanism. In our previous study, we found that SMAD4 deletion mutation pancreatic cancer cells were more sensitive to ferroptosis induced by erastin, compared with SMAD4 wild type cells. In-depth study found that GPX1 regulates the hyper-autophagy and ferroptosis in SMAD4 mutant pancreatic cancer by activating p62-Keap1-NRF2 pathway. Thus, we suggest that there is a new molecular mechanism as an axis of “GPX1-p62-Keap1-NRF2”to take effect. Next, we intend to further carry out some researches to disturb this functional axis by in vitro and in vivo assays and validation of clinical specimens, to verify the role of this new functional axis in autophagy and ferroptosis mechanism of SMAD4 deletion mutation pancreatic cancer, which could help effectively improving the unfavorable prognosis and providing a potential target for individualized therapy in pancreatic cancer.