<br>Reprimo （RPRM）在辐射诱导的脑损伤中通过 CREB-Nrf2/SCD1 通路介导神经元铁死亡,Free Radical Biology and Medicine

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Reprimo （RPRM）在辐射诱导的脑损伤中通过 CREB-Nrf2/SCD1 通路介导神经元铁死亡
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2024-01-24 , DOI: 10.1016/j.freeradbiomed.2024.01.021
Wenyu Shi ₁ , Jin Wang ₂ , Zhaojun Li ₂ , Shuning Xu ₂ , Jingdong Wang ₂ , Liyuan Zhang ₃ , Hongying Yang ₄

Affiliation

Department of Radiotherapy and Oncology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province, 215123, PR China.
Department of Radiotherapy and Oncology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, PR China; Institute of Radiotherapy & Oncology of Soochow University, Suzhou, Jiangsu Province, 215004, PR China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province, 215123, PR China; Institute of Radiotherapy & Oncology of Soochow University, Suzhou, Jiangsu Province, 215004, PR China.

已发现神经元铁死亡会导致退行性脑疾病以及创伤性和出血性脑损伤，但放射诱导性脑损伤（RIBI）是颅放射治疗对原发性和转移性脑肿瘤的严重有害作用，是否涉及神经元铁死亡仍不清楚。我们最近发现，肿瘤抑制基因 reprimo （RPRM）的缺失可改善 RIBI，其中它对神经元的保护作用是潜在机制之一。在这项研究中，我们发现全脑照射（WBI）诱导小鼠脑铁死亡，表现为线粒体形态改变、铁积累、脂质过氧化和谷胱甘肽过氧化物酶 4 （GPX4）水平显着降低。此外，电离照射（IR）诱导的海马铁死亡主要发生在神经元中。有趣的是，RPRM 缺失保护大脑和原代神经元免受 IR 诱导的铁死亡。从机制上讲，RPRM 缺失通过逆转铁储存蛋白铁蛋白重链（Fth）、铁蛋白轻链（Ftl）和铁输入铁转铁蛋白受体 1 （Tfr1）表达的显着增加，以及增强铁输出蛋白铁转运蛋白（Fpn）的表达，阻止铁积累IR 后。RPRM 缺失还通过消除 IR 诱导的 GPX4 和硬脂酰辅酶 A 去饱和酶-1 （SCD1）的还原来抑制脂质过氧化。重要的是，RPRM 缺失恢复甚至增加了受照射神经元中核因子、红细胞 2 样 2 （Nrf2）的表达。最重要的是，发现受损的环腺苷酸反应元件（CRE）结合蛋白（CREB）信号传导是照射后 Nrf2 和 SCD1 下调的原因，具体来说，RPRM 与 CREB 结合并促进其在 IR 后降解，导致 CREB 蛋白水平降低，进而下调 Nrf2 和 SCD1。因此，RPRM 缺失通过对 CREB 的影响恢复了 Nrf2 和 SCD1。综上所述，神经元铁死亡参与 RIBI，RPRM 缺失通过恢复 CREB-Nrf2/SCD1 通路来防止 IR 诱导的神经元铁死亡。

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Reprimo (RPRM) mediates neuronal ferroptosis via CREB-Nrf2/SCD1 pathways in radiation-induced brain injury

Neuronal ferroptosis has been found to contribute to degenerative brain disorders and traumatic and hemorrhagic brain injury, but whether radiation-induced brain injury (RIBI), a critical deleterious effect of cranial radiation therapy for primary and metastatic brain tumors, involves neuronal ferroptosis remains unclear. We have recently discovered that deletion of reprimo (RPRM), a tumor suppressor gene, ameliorates RIBI, in which its protective effect on neurons is one of the underlying mechanisms. In this study, we found that whole brain irradiation (WBI) induced ferroptosis in mouse brain, manifesting as alterations in mitochondrial morphology, iron accumulation, lipid peroxidation and a dramatic reduction in glutathione peroxidase 4 (GPX4) level. Moreover, the hippocampal ferroptosis induced by ionizing irradiation (IR) mainly happened in neurons. Intriguingly, RPRM deletion protected the brain and primary neurons against IR-induced ferroptosis. Mechanistically, RPRM deletion prevented iron accumulation by reversing the significant increase in the expression of iron storage protein ferritin heavy chain (Fth), ferritin light chain (Ftl) and iron importer transferrin receptor 1 (Tfr1), as well as enhancing the expression of iron exporter ferroportin (Fpn) after IR. RPRM deletion also inhibited lipid peroxidation by abolishing the reduction of GPX4 and stearoyl coenzyme A desaturase-1 (SCD1) induced by IR. Importantly, RPRM deletion restored or even increased the expression of nuclear factor, erythroid 2 like 2 (Nrf2) in irradiated neurons. On top of that, compromised cyclic AMP response element (CRE)-binding protein (CREB) signaling was found to be responsible for the down-regulation of Nrf2 and SCD1 after irradiation, specifically, RPRM bound to CREB and promoted its degradation after IR, leading to a reduction of CREB protein level, which in turn down-regulated Nrf2 and SCD1. Thus, RPRM deletion recovered Nrf2 and SCD1 through its impact on CREB. Taken together, neuronal ferroptosis is involved in RIBI, RPRM deletion prevents IR-induced neuronal ferroptosis through restoring CREB-Nrf2/SCD1 pathways.

更新日期：2024-01-24

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