Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time‐course changes of ferroptosis‐related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin‐1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron‐specific Fth conditional knockout (Fth‐KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth‐KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth‐KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth‐mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti‐ferroptosis provides a potential therapeutic target for treating TBI.

中文翻译：

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神经元中铁蛋白H的缺失抵消了褪黑激素对创伤性脑损伤诱导的铁死亡的保护作用

越来越多的证据表明，铁死亡可能在创伤性脑损伤 (TBI) 的病理生理过程中很重要。作为松果体的主要激素，褪黑激素对 TBI 具有许多有益作用，但没有关于褪黑激素对 TBI 后铁死亡的影响的信息。正如预期的那样，TBI 导致同侧皮质中铁死亡相关分子表达和铁积累的时间过程变化。重要的是，我们发现用褪黑激素治疗有效地挽救了 TBI 诱发了上述变化并改善了与载体相比的功能缺陷。铁死亡抑制剂 liproxstatin-1 也获得了类似的结果。此外，褪黑激素的保护作用可能取决于褪黑激素受体 1B (MT2)。尽管铁蛋白通过储存过量的细胞铁在铁代谢中起着至关重要的作用，但其在大脑中的确切功能以及它是否涉及褪黑激素的神经保护作用仍未得到探索。考虑到铁蛋白 H (Fth) 主要在神经元中表达，并且小鼠中的Fth诱导早期胚胎致死，然后我们生成了神经元特异性Fth条件敲除 ( Fth ‐KO) 小鼠，它们是有活力且可育的，但铁代谢发生了改变。此外，Fth- KO 小鼠在 TBI 后更容易发生铁死亡，褪黑激素的神经保护作用在Fth- KO 小鼠中基本消失。体外实验进一步证实了上述结果。总之，这些数据表明褪黑激素至少部分通过抑制神经元Fth-TBI 后介导的铁死亡，支持褪黑激素是一种极好的铁死亡抑制剂的观点，其抗铁死亡为治疗 TBI 提供了潜在的治疗靶点。