Han YaoNan, Wang XingTong, Yu DeShui
Department of Orthopedics, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province 121000, China.
Department of Orthopedics, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province 121000, China.
Cell Signal. 2025 Oct;134:111930. doi: 10.1016/j.cellsig.2025.111930. Epub 2025 Jun 12.
Spinal cord injury (SCI) is a serious central nervous system disease. Ferroptosis is one of the major causes of spinal cord neurological loss, and targeting ferroptosis is a promising therapeutic strategy. Roflumilast has shown promising applications in the treatment of neurological diseases due to its potent anti-inflammatory and anti-oxidative stress effects. This study aimed to investigate whether roflumilast could inhibit neuronal ferroptosis to improve motor function after SCI in rats. In vitro experiments, we found that roflumilast significantly increased cell survival in an in vitro ferroptosis model, improved mitochondrial function, reduced intracellular iron, reactive oxygen species (ROS), and lipid peroxides accumulation as well as the expression of the pro-ferroptosis proteins, long-chain acyl-coenzyme A synthase 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2), and increased the expression of ferroptosis-inhibitory protein glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) expression. Mechanistically, these protective effects were achieved by activating AMP-dependent protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and were attenuated when AMPK signaling was blocked. In vivo experiments, roflumilast attenuated spinal cord tissue damage, increased the number of motor neuron survivors, and improved motor function after SCI in rats. Overall, activation of AMPK/Nrf2/HO-1 signaling by roflumilast attenuated neuronal ferroptosis and improved motor function after SCI in rats.
脊髓损伤（SCI）是一种严重的中枢神经系统疾病。铁死亡是脊髓神经功能丧失的主要原因之一，针对铁死亡进行治疗是一种很有前景的治疗策略。罗氟司特因其强大的抗炎和抗氧化应激作用，在神经疾病治疗中已显示出有前景的应用。本研究旨在探讨罗氟司特是否能抑制大鼠脊髓损伤后神经元的铁死亡以改善运动功能。在体外实验中，我们发现罗氟司特在体外铁死亡模型中显著提高细胞存活率，改善线粒体功能，减少细胞内铁、活性氧（ROS）和脂质过氧化物的积累，以及促铁死亡蛋白长链酰基辅酶A合成酶4（ACSL4）和前列腺素内过氧化物合酶2（PTGS2）的表达，并增加铁死亡抑制蛋白谷胱甘肽过氧化物酶4（GPX4）和铁蛋白重链1（FTH1）的表达。机制上，这些保护作用是通过激活AMP依赖的蛋白激酶（AMPK）/核因子E2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）信号通路实现的，当AMPK信号通路被阻断时，这些保护作用减弱。在体内实验中，罗氟司特减轻了大鼠脊髓损伤后的脊髓组织损伤，增加了运动神经元存活数量，并改善了运动功能。总体而言，罗氟司特激活AMPK/Nrf2/HO-1信号通路可减轻大鼠脊髓损伤后神经元的铁死亡并改善运动功能。
