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

  • Stem Cell Res Ther. 2025 Jul 1;16(1):340. doi: 10.1186/s13287-025-04453-9.
Yuzhu Xu  #  1 ,  Lele Zhang  2 ,  Mingliang Ji  3 ,  Jun Lu  #  4
Affiliations
  • 1. Department of Spine Center, Orthopedics Department, Medical School, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing, 210009, Jiangsu, China. [email protected].
  • 2. Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 3. The Center of Joint and Sports Medicine, Orthopedics Department, Medical School, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing, 210009, Jiangsu, China.
  • 4. The Center of Joint and Sports Medicine, Orthopedics Department, Medical School, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing, 210009, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 40598356 DOI: 10.1186/s13287-025-04453-9
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.

Keywords
Bone marrow mesenchymal stem cells (BMSCs); F-box only protein 22 (FBXO22); Ferroptosis; Intervertebral disc degeneration (IVDD); Prominin-2.
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