Prominin-2/FBXO22/BACH1轴保护骨髓间充质干细胞免受叔丁基过氧化氢诱导的铁死亡，并改善椎间盘退变。

Prominin-2/FBXO22/BACH1 axis protects bone marrow mesenchymal stem cells against TBHP-induced ferroptosis and ameliorates intervertebral disc degeneration.

作者信息

Xu Yuzhu, Zhang Lele, Ji Mingliang, Lu Jun

机构信息

Department of Spine Center, Orthopedics Department, Medical School, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing, 210009, Jiangsu, China.

Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

出版信息

Stem Cell Res Ther. 2025 Jul 1;16(1):340. doi: 10.1186/s13287-025-04453-9.

DOI:10.1186/s13287-025-04453-9

PMID:40598356

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12220210/

Abstract

BACKGROUND

Our preliminary research has revealed that Prominin-2 overexpression effectively guarded against oxidative stress (OS)-induced ferroptosis by decreasing BTB and CNC homolog 1 (BACH1) expression, thus promoting bone marrow mesenchymal stem cells (BMSCs) survival under the OS microenvironments in degenerative discs.

METHODS

In this study, we probed how Prominin-2 controls the BACH1 expression in OS-induced BMSC ferroptosis. We then evaluated the efficiency of targeted Prominin-2/BACH1 pathway in BMSCs in treating degenerative nucleus pulposus cells (NPCs) and intervertebral disc degeneration (IVDD).

RESULTS

Using lentivirus infection and Western Blot, we observed that F-box only protein 22 (FBXO22) levels decreased in OS-induced BMSCs while overexpressing Prominin-2 restored its expression and pharmacological inhibition of FBXO22 impaired Prominin-2-mediated BACH1 degradation. The pull-down assay further confirmed the essential role of FBXO22 in the degradation of BACH1 promoted by Prominin-2. FBXO22 overexpression suppressed BMSCs' ferroptosis, and FBXO22 activity enhancer TBE56 (biotinylated TBE31) could further improve Prominin-2-overexpressed BMSCs' viability under OS circumstances. Finally, in vitro co-culture and in vivo studies illustrated that engraftment of Prominin-2-overexpressed BMSCs pre-treated by TBE56 enhanced the treatment efficiency of BMSCs for degenerative NPCs and rats' IVDD.

CONCLUSIONS

Our data proposed a novel treatment strategy targeting the ferroptosis of BMSCs for treating IVDD by regulating FBXO22 in Prominin-2-overexpressed BMSCs.

摘要

背景

我们的初步研究表明，Prominin-2过表达通过降低BTB和CNC同源物1（BACH1）的表达，有效抵御氧化应激（OS）诱导的铁死亡，从而促进退变椎间盘OS微环境下骨髓间充质干细胞（BMSCs）的存活。

方法

在本研究中，我们探究了Prominin-2如何控制OS诱导的BMSC铁死亡中BACH1的表达。然后，我们评估了BMSCs中靶向Prominin-2/BACH1通路治疗退变髓核细胞（NPCs）和椎间盘退变（IVDD）的效果。

结果

通过慢病毒感染和蛋白质免疫印迹法，我们观察到在OS诱导的BMSCs中，F盒蛋白22（FBXO22）水平降低，而过表达Prominin-2可恢复其表达，并且对FBXO22的药理抑制会损害Prominin-2介导的BACH1降解。下拉实验进一步证实了FBXO22在Prominin-2促进的BACH1降解中的重要作用。FBXO22过表达抑制了BMSCs的铁死亡，并且FBXO22活性增强剂TBE56（生物素化的TBE31）可进一步提高OS条件下过表达Prominin-2的BMSCs的活力。最后，体外共培养和体内研究表明，用TBE56预处理的过表达Prominin-2的BMSCs移植可提高BMSCs对退变NPCs和大鼠IVDD的治疗效率。