低血糖可导致严重脑损伤，但其病理性细胞死亡的形式及机制尚不完全清楚。铁死亡是由铁依赖的氧化损伤引起的非凋亡细胞死亡，在脑损伤发生发展过程中起重要作用。我们前期发现过氧化物酶体增殖物激活受体γ（PPARγ）对严重低血糖造成的血脑屏障破坏具有保护作用；PPARγ调控Nrf2参与低血糖脑损伤过程，但其分子机制尚不明确。本研究拟在分子-细胞-动物水平，以低血糖诱导PPARγ水平下降为切入点，首先在确认铁死亡参与低血糖脑损伤的基础上，明确PPARγ与铁死亡的相关性；进一步通过研究Nrf2-RIPK1通路的水平变化，证实PPARγ对Nrf2调控作用能引起Nrf2水平下降，进而激活铁死亡通路，引发神经元损伤；最终验证上调PPARγ干预铁死亡对低血糖脑损伤的保护作用，为阐明低血糖脑损伤的分子机制和干预靶点提供新的研究思路和药物靶点。

Hypoglycemia can cause severe brain damage. However, the form and mechanism of cell death are still not clear. Ferroptosis is a non-apoptotic cell death caused by iron-dependent oxidative damage and plays an important role in the development of brain injury. We have previously found that peroxisome proliferator-activated receptor gamma (PPARγ) has a protective effect on blood-brain barrier disruption caused by severe hypoglycemia; PPARγ mediates Nrf2 involvement in hypoglycemic brain injury, but its molecular mechanism is still unclear. This study intends to reduce the level of PPARγ induced by hypoglycemia at the molecular-cell-animal level. In the research, based on confirming that iron death is involved in hypoglycemic brain injury, we will study the molecular mechanism of PPARγ involved in the ferroptosis induced by hypoglycemia at the molcecular-cellular-animal level. Firstly, the confirmation of PPARγ associated with ferroptosis would be proved. Next, by studying the changes of Nrf2-RIPK1, we would find the regulation of PPARγ on Nrf2 can cause the decrease of PPARγ level, and then activate the pathway of ferroptosis triggering neuronal damage. Finally, we will verify whether the up-regulation of PPARγ could have protective effects against ferroptosis in hypoglycemic brain injury. In summary, this project would put forward a novel pathophysiological mechanism and therapeutic target under the ferroptosis in hypoglycemia.