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

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.