2024年4月2日出版的《细胞—代谢》杂志发表了中国科学家的一项最新研究成果。华中科技大学的Kehan Song、Feng Li团队发现，临床阶段Nrf2激活剂通过铁鸟氨酸轴抑制破骨细胞分化。

据了解，通过小分子激活Nrf2是治疗绝经后骨质疏松症的一种很有前途的策略。然而，目前还没有批准用于治疗慢性疾病的Nrf2激活剂，Nrf2调控破骨细胞分化的下游机制尚不清楚。

该课题组人员发现bitopertin，一种临床阶段甘氨酸摄取抑制剂，通过激活Nrf2抑制破骨细胞分化并改善卵巢切除术诱导的骨质流失。从机制上讲，bitopertin与Keap1 Kelch结构域相互作用，减少Keap1-Nrf2结合，导致Nrf2泛素化和降解减少。在小鼠和人类受试者中，与临床批准的Nrf2激活剂相比，bitopertin相关不良事件更少。

此外，Nrf2转录激活铁转运蛋白编码基因Slc40a1，以降低破骨细胞内的铁水平。Nrf2缺失或补铁会上调鸟氨酸代谢酶Odc1，从而降低鸟氨酸水平，从而促进破骨细胞分化。总的来说，他们的发现确定了一种新的临床阶段Nrf2激活剂，并提出了一种新的Nrf2-铁鸟氨酸在破骨细胞中的代谢轴。

附：英文原文

Title: A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Author: Yimin Dong, Honglei Kang, Renpeng Peng, Zheming Liu, Fuben Liao, Shi-an Hu, Weizhong Ding, Pengju Wang, Pengchao Yang, Meipeng Zhu, Sibo Wang, Minglong Wu, Dawei Ye, Xin Gan, Feng Li, Kehan Song

Issue&Volume: 2024-04-02

Abstract: Activating Nrf2 by small molecules is a promising strategy to treat postmenopausalosteoporosis. However, there is currently no Nrf2 activator approved for treatingchronic diseases, and the downstream mechanism underlying the regulation of Nrf2 onosteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stageglycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-inducedbone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitinationand degradation. Bitopertin is associated with less adverse events than clinicallyapproved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionallyactivates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementationupregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels andthereby promotes osteoclast differentiation. Collectively, our findings identify anovel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolicaxis in osteoclasts.

DOI: 10.1016/j.cmet.2024.03.005

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00084-6