糖尿病性勃起功能障碍（ED）的药物治疗效果不佳，这与海绵体平滑肌细胞、内皮细胞、海绵体神经等细胞的死亡和功能下降有关。铁死亡是一种新发现的细胞死亡形式，参与了氧化应激引起的细胞损伤，许多糖尿病的并发症与铁死亡相关。谷胱甘肽过氧化物酶4（GPX4）是细胞内对抗铁死亡的关键酶，申请者预实验发现糖尿病可减少海绵体内GPX4的表达，增加铁死亡，从而影响细胞的活力和功能。因此我们推测GPX4下调所诱导的铁死亡可能参与了糖尿病性ED的发生。CRISPRa SAM是一种新兴的基因激活技术，可高效、稳定地激活目的基因。本项目拟在体内、体外两个水平，利用CRISPRa SAM和RSL3（GPX4抑制剂）分别上调和下调阴茎海绵体、海绵体内皮细胞和平滑肌细胞中GPX4的表达，研究其对铁死亡及勃起功能的影响，从而阐明GPX4下调所诱导的铁死亡在糖尿病性ED中的作用和机制,为糖尿病性ED的治疗提供新的作用靶点。

Diabetic erectile dysfunction (ED) has bad response to drug treatment. This is related to the death and dysfunction of cavernous smooth muscle cells, endothelial cells and cavernous nerve. Ferroptosis is a novel cell death that is involved in the cellular damage caused by oxidative stress. Many diabetic complications are associated with ferroptosis. Glutathione peroxidase 4 (GPX4) is an important intracellular inhibitor of ferroptosis. In our preliminary experiments, we found diabetes could reduce the expression of GPX4 and increase ferroptosis in cavernosum, thereby impairing cell viability and function. We thereby speculate that the ferroptosis induced by GPX4 downregulation is related to diabetic ED. CRISPRa SAM system is a cutting-edge gene-activating technology which can activate target gene efficiently and steadily. Current study is to upregulate and downregulate the expression of GPX4 with CRISPRa SAM system and RSL3 (GPX4 inhibitor) respectively in cavernosum, cavernous endothelial cells and smooth muscle cells in vivo and in vitro, and to explore its effects on ferroptosis and erectile function, thereby clarifying the effect and mechanism of ferroptosis induced by GPX4 downregulation on diabetic ED. This study will provide a novel treating target for diabetic ED.