脊髓损伤（SCI）是脊柱手术中极具残疾性的一种情况，导致神经元损伤和继发性炎症。铁死亡是一种非凋亡性细胞死亡，是最近被发现的，主要通过铁依赖性和脂质衍生的活性氧积累标记，并伴随着线粒体萎缩和膜密度增加等形态学改变。双氢乳酸脱氢酶（DHODH）是铁死亡的有力抑制剂，并已证明在肿瘤细胞中抑制细胞铁死亡，但它是否可以抑制脊髓损伤后的神经损伤仍不明确。 本研究采用大鼠脊髓损伤模型和诱导PC12细胞的erastin，分别在体内和体外观察DHODH对神经元铁死亡的影响，使用分子和组织学方法结合，评估体内和体外的铁死亡情况并探索可能的机制。首先，我们确认了脊髓损伤后存在神经元铁死亡，DHODH减轻了脊髓损伤后的神经损伤。其次，我们展示了DHODH抑制铁死亡相关分子激活及减少脂质过氧化物和线粒体损伤的分子证据，从而降低神经元铁死亡。进一步的分析表明，P53/ALOX15可能是DHODH调节的其中一个机制。重要的是，我们确定DHODH通过抑制P53来抑制ALOX15表达。 我们的发现揭示了DHODH在脊髓损伤后神经元铁死亡中的新功能，提示一种唯一的治疗靶点，以缓解脊髓损伤的疾病过程。© 2023 The Authors. CNS Neuroscience＆Therapeutics published by John Wiley＆Sons Ltd.

Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non-apoptotic type of cell death that has only recently been identified, which is marked primarily by iron-dependent and lipid-derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous.In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin-induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro.First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis-related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53.Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.