PPARγ-ACSL4稳定细胞脂质膜抑制脑出血后神经元ferroptosis的机制研究

铁死亡（Ferroptosis）是一种依赖于铁离子，脂质过氧化产物蓄积为特征的新型细胞死亡方式，在脑出血（ICH）继发性神经损伤中起重要作用，其调控机制尚未明确。我们前期研究发现：人脑血肿周围组织中PPARγ通路和脂肪酸代谢通路激活；PPARγ激活可抑制神经元铁死亡并下调ACSL4的表达。研究表明ACSL4特异性增加含脂质膜的多不饱和脂肪酸（PUFAs）含量，细胞易于发生铁死亡。目前未见PPARγ调控ICH后神经元铁死亡的报道。据此我们提出假说：PPARγ-ACSL4降低神经元脂质膜中PUFAs含量，稳定脂质膜，抑制神经元铁死亡。本课题拟：探讨PPARγ在ICH后的激活特点；明确PPARγ对神经元脂质膜PUAFs的调控；揭示PPARγ-ACSL4抑制神经元铁死亡的机制。本研究将从稳定脂质膜这个新视点探讨ICH后神经元铁死亡干预策略，为ICH继发性神经损伤的治疗提供新思路。

Ferroptosis is a new form of regulated cell death characterized by iron-dependent and accumulation of lipid peroxidation. Ferroptosis plays an important role in the pathological of secondary brain injury after ICH. However, the mechanism that regulates ICH-induced neuronal ferroptosis needs to be further clarified. Our previous research found that: PPARγ pathways and fatty acid metabolism pathways were activated in the perihematomal tissue of human brain; PPARγ inhibit neuronal ferroptosis and down-regulate the expression of ACSL4. Studies have shown that ACSL4 specifically increases the content of polyunsaturated fatty acids (PUFAs) of lipid-containing membranes, then cells are more prone to undergo ferroptosis. There is no report that PPARγ regulates neuronal ferroptosis after ICH. So, we put forward the hypothesis: PPARγ-ACSL4 reduces the content of PUFAs of the lipid membrane of neurons, stabilizes the lipid membrane, and inhibits neuronal ferroptosis. This project intends to explore the activation characteristics of PPARγ after ICH, to clarify the regulation of PPARγ on PUAFs in neuronal lipid membranes, to reveal the mechanism of PPARγ-ACSL4 stabilized cell lipid membrane to inhibit neuronal ferroptosis. This study will explore the intervention strategy of neuronal ferroptosis after ICH from a novel perspective of stabilizing lipid membranes, and provide new ideas for the treatment of secondary brain injury after ICH.