过氧化物还原酶Peroxiredoxin 2调控ROS-ASK1-p38 MAPK信号通路抑制蛛网膜下腔出血后神经元铁死亡的机制研究

Ferroptosis is the predominant form of programmed cell death following cerebral hemorrhagic stroke. Our previous study found that neuronal ferroptosis is common after subarachnoid hemorrhage (SAH), but its regulatory mechanism is still unclear. Ferroptosis is mainly characterized by iron-dependent reactive oxygen species (ROS) aggregation and activation of the ASK1-p38 MAPK signaling pathway. In the central nervous system, peroxiredoxin 2 (Prx2) is mainly distributed in neurons, and its expression is significantly increased after SAH, which has the effect of inhibiting neuronal ferroptosis. Prx2 is both a peroxide scanvanger; it is also a molecular chaperone involved in the regulation of protein function. Based on this, we hypothesized that after SAH, Prx2 can not only decompose ROS, but also inhibit the activation of ASK1, so that regulates ROS-ASK1-p38 MAPK signaling pathway, thereby inhibiting neuronal ferroptosis. This study intends to combine the in vivo and in vitro models to elucidate the mechanism of Prx2 in inhibiting neuronal ferroptosis after SAH from two aspects: enzyme activity and protein interaction.

铁死亡（Ferroptosis）是脑出血性卒中后神经元程序性死亡的主要形式，我们的前期研究发现蛛网膜下腔出血（SAH）后神经元铁死亡现象普遍存在，但其调控机制尚不明确。铁死亡主要表现为铁依赖的活性氧自由基（ROS）聚集，以及ASK1-p38 MAPK信号通路的激活等。在中枢神经系统中，过氧化物还原酶2（Prx2）主要分布于神经元，且在SAH后表达显著升高，具有抑制神经元铁死亡的作用。Prx2既是一种过氧化物酶，可以分解ROS；也是一种分子伴侣，参与蛋白功能的调控。据此我们提出假说：SAH后，Prx2不仅可以通过分解ROS，还可以通过抑制ASK1的激活，从两个节点上调控ROS-ASK1-p38 MAPK信号通路，从而抑制神经元铁死亡。本课题拟采用体内与体外模型相结合，分别从酶活性和蛋白相互作用两个方面阐明Prx2在抑制SAH后神经元铁死亡中的作用机制。

蛛网膜下腔出血（SAH）后早期脑损伤是影响患者预后的重要因素，其中神经元的铁死亡直接影响了脑功能的恢复，但具体机制仍不明确。我们研究发现：SAH后患者脑脊液中的Prx2是患者预后的潜在生物标志物，其表达水平越高，患者预后越差。同时，SAH后脑组织中PDK4水平显著上升，可以抑制ROS-ASK1/p38信号通路，减轻神经元氧化应激，抑制神经元铁死亡。本课题通过对临床患者样本检测、动物试验和体外试验的方法，聚焦神经元内氧化应激，探讨ROS-ASK1/p38信号通路在神经元铁死亡中的作用机制。通过此项研究，将有助于深入理解SAH后神经元铁死亡的分子机制，为SAH的临床治疗提供新的靶点。

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