Cold-inducible RNA binding protein (CIRBP), a stress response protein, protects cells from mild hypothermia or hypoxia by stabilizing specific mRNAs and promoting their translation. Neurons subjected to hypobaric hypoxia insult trigger various cell death programs. One of these is ferroptosis, a novel non-apoptotic form of programmed cell death, which is characterized by excessive iron ion accumulation and lipid peroxidation. Here, we establish that CIRBP can regulate neuronal ferroptosis both in vivo and in vitro. We observe that hypoxia leads to neuronal death via intracellular ferrous iron overload and impaired antioxidant systems, accompanied by suppressed CIRBP expression. Genetic enrichment of CIRBP in hippocampal neurons CIRBP^Tg mice bred with Emx1-Cre mice attenuates hypoxia-induced cognitive deficits and neuronal degeneration. Mechanistically, CIRBP alleviates neuronal ferroptosis and intracellular ferrous ion accumulation by binding to the mitochondrial ferritin (FTMT) 3’UTR to stabilize mRNA and promote its translation. Our novel study shows the critical role of CIRBP in the progression of ferroptosis, and provides promising therapeutic target for hypoxia-induced neurological diseases.

冷诱导 RNA 结合蛋白 (CIRBP) 是一种应激反应蛋白，通过稳定特定 mRNA 并促进其翻译，保护细胞免受轻度低温或缺氧的影响。遭受低压缺氧损伤的神经元会触发各种细胞死亡程序。其中之一是铁死亡，这是一种新型的非凋亡形式的程序性细胞死亡，其特征是铁离子过度积累和脂质过氧化。在这里，我们确定 CIRBP 可以在体内和体外调节神经元铁死亡。我们观察到缺氧通过细胞内亚铁过载和抗氧化系统受损导致神经元死亡，并伴有 CIRBP 表达抑制。海马神经元中 CIRBP 的遗传富集与 Emx1-Cre 小鼠交配的 CIRBP ^Tg小鼠可减轻缺氧引起的认知缺陷和神经元变性。从机制上讲，CIRBP 通过与线粒体铁蛋白 (FTMT) 3'UTR 结合来稳定 mRNA 并促进其翻译，从而减轻神经元铁死亡和细胞内亚铁离子积累。我们的新研究表明了 CIRBP 在铁死亡进展中的关键作用，并为缺氧引起的神经系统疾病提供了有希望的治疗靶点。