Key Takeaways & Executive Findings
- •• HSF1 transcriptionally activates PROM2, elevating Prominin-2 expression to protect BMSCs from ferroptosis. • Prominin-2 promotes BACH1 ubiquitination and degradation, reversing TBHP-induced downregulation of GLS. • Targeting the Prominin-2/BACH1/GLS axis enhances BMSC survival post-transplantation and mitigates IVDD progression. • Provides novel mechanistic insights and potential therapeutic targets for improving BMSC-based IVDD therapy under oxidative stress.
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.
1. Introduction
It has been widely recognized that intervertebral disc degeneration (IVDD) predominantly causes chronic low back pain and disability [1]. Up to now, supplementation of transplanted bone mesenchymal stem cells (BMSCs) has manifested therapeutic efficiency on IVDD in basic and preclinical science research [2, 3]. Transplantation of BMSCs into degenerative intervertebral discs (IVDs) exerts therapeutic effects via a diversity of mechanisms, e.g., reducing functional cells’ death, differentiating into nucleus pulposus-like cells, lessening the expression of extracellular matrix, suppressing the release of pro-inflammatory cytokines [2]. Despite significant achievements in this area, unsolved weaknesses still hinder the therapeutic benefits of BMSCs. Among these restrictions, inferior BMSC retention in the oxidative stress (OS) microenvironment is a significant cause of BMSCs’ loss and inadequate therapeutic advantages after transplantation into degenerative IVDs [4, 5]. Therefore, it is urgently required to develop suitable strategies to enhance BMSC retention in the OS microenvironment of degenerative IVDs.
It is known that OS participates in the pathogenesis of IVDD, which is attributed to redox unbalance [6]. The process of IVDD increased reactive oxygen species (ROS) production and added to the harsh and complex microenvironment of degenerative IVDs. When withstanding OS exceeds their maximal adaptability range in IVDs, engrafted BMSCs will undergo an inevitable cell death procedure, instead of stably exerting therapeutic effects. Hence, improving the survival rate of BMSCs in OS circumstances is a crucial way to enhance their retention and fortify therapeutic benefits. We have previously elaborated on the molecular mechanisms of ferroptosis in mesenchymal stem cells (MSCs), emphasizing that it is an iron-reliant, OS-induced regulated cell death [4]. The persistent state of OS would overwhelm BMSCs’ antioxidant defense after being transplanted into degenerative IVDs, eventually bringing out oxidative disruptions of the intracellular microenvironment, thereby initiating ferroptosis. Our prior experimental results confirmed that ferroptosis is mainly responsible for BMSCs’ low survival in the early stages of in vitro ROS stress or after implantation into degenerative IVDs [5].
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Yuzhu Xu, Lele Zhang, Xuanfei Xu, Yuao Tao, Pengfei Xue, Yuntao Wang, Renjie Chai, Xiaotao Wu (2026). Targeting prominin-2/BACH1/GLS pathway to inhibit oxidative stress-induced ferroptosis of bone mesenchymal stem cells. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04326-1
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Frequently Asked Questions
What is the role of Prominin-2 in BMSC ferroptosis?
Prominin-2 protects BMSCs from ferroptosis by decreasing cellular Fe2+ content and inhibiting BACH1 expression, thereby promoting cell survival under oxidative stress.
How does the Prominin-2/BACH1/GLS pathway regulate ferroptosis?
Prominin-2 promotes BACH1 ubiquitination and degradation, which reverses TBHP-induced downregulation of GLS, a key enzyme that protects BMSCs against ferroptosis.
What is the significance of targeting this pathway for IVDD therapy?
Targeting the Prominin-2/BACH1/GLS axis improves BMSC survival post-transplantation and mitigates IVDD progression by inhibiting ferroptosis, offering potential therapeutic targets for enhancing BMSC-based treatments.
What experimental models were used in this study?
The study employed both in vitro and in vivo experiments, including TBHP-induced ferroptosis models and transplantation into degenerative IVDs, to elucidate the molecular mechanisms.
What is the clinical relevance of this research?
The findings provide new mechanistic insights into BMSC ferroptosis regulation, which could lead to strategies to improve the survival of engrafted BMSCs under oxidative stress conditions, enhancing the efficacy of cell therapy for IVDD.
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