Targeting prominin-2/BACH1/GLS pathway to inhibit oxidative stress-induced ferroptosis of bone mesenchymal stem cells

  • Stem Cell Res Ther. 2025 Apr 29;16(1):213. doi: 10.1186/s13287-025-04326-1.
Yuzhu Xu  1 ,  Lele Zhang  1 ,  Xuanfei Xu  2 ,  Yuao Tao  1 ,  Pengfei Xue  1 ,  Yuntao Wang  1 ,  Renjie Chai  3 ,  Xiaotao Wu  4
Affiliations
  • 1. Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing City, 210009, Jiangsu Province, China.
  • 2. Department of Nuclear Medicine, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, Jiangsu, China.
  • 3. Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210009, Jiangsu, China.
  • 4. Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing City, 210009, Jiangsu Province, China. [email protected].
PMID: 40301995 DOI: 10.1186/s13287-025-04326-1
Abstract

Suppressing bone mesenchymal stem cell (BMSC) Ferroptosis is expected to optimize BMSCs-based therapy for intervertebral disc degeneration (IVDD). Our previous study revealed that Prominin-2 could protect against Ferroptosis by decreasing cellular Fe2+ content and inhibiting transcription regulator protein BACH1 (BACH1) expression. In this study we probed the molecular mechanisms underlying the Prominin-2/BACH1 pathway in BMSC Ferroptosis. Using an array of in vitro and in vivo experiments we found that heat shock factor protein 1 (HSF1) activates PROM2 (encoding protein Prominin-2) transcription and elevated Prominin-2 expression. Furthermore, we showed that Prominin-2 attenuates Ferroptosis induced by tert-butyl hydroperoxide (TBHP) through promoting BACH1 ubiquitination and degradation. Inhibition of BACH1 expression reversed TBHP-stimulated down expression of Glutaminase kidney isoform, mitochondrial (GLS), which plays a crucial role in protecting BMSCs against Ferroptosis. Targeting the Prominin-2/BACH1 axis has also been shown to improve BMSC survival post-transplantation and mitigate IVDD progression by inhibiting Ferroptosis. Our results support a new mechanistic insight into the regulation of the Prominin-2/BACH1/GLS pathway in BMSC Ferroptosis. These finding could lead to potential therapeutic targets to improve the survival of engrafted BMSCs under oxidative stress circumstances.

Keywords
BTB and CNC homolog 1 (BACH1); Bone marrow mesenchymal stem cells (BMSCs); Ferroptosis; Glutaminase kidney isoform; Mitochondrial (GLS); Prominin-2.
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