Xu Yuzhu, Qian Zhanyang, Ji Mingliang, Lu Jun
Department of Spine Center, Orthopedics Department, Zhongda Hospital, Southeast University, No. 87 DingJiaQiao, GuLou District, Nanjing City, 210009, Jiangsu Province, China.
Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong First People's Hospital, Medical School of Nantong University, Nantong, 226000, Jiangsu, China.
Apoptosis. 2026 Jan 13;31(1):45. doi: 10.1007/s10495-026-02273-7.
Intervertebral disc degeneration (IVDD) is a predominant cause of low back pain, and mesenchymal stem cell (MSC) transplantation represents a promising therapeutic strategy. However, its efficacy is severely limited by the harsh oxidative microenvironment of the degenerative disc, which rapidly triggers ferroptosis, an iron-dependent form of cell death, in transplanted MSCs.
This review critically appraised current ferroptosis-inhibition strategies, highlighting their transient or single-axis limitations. We then synthesized a hierarchical framework for engineering robust MSC resistance, progressing from dual-target gene circuits and genetic-pharmacological alliances to smart, protective biomaterial niches.
Conventional approaches provide only partial protection. In contrast, advanced multi-layered strategies, including dual-target gene circuits (e.g., the Prominin-2/FBXO22/BACH1 axis) potentiated by genetic-pharmacological alliances (e.g., with TBE56), confer superior, cell-intrinsic resilience, increasing MSC survival by approximately 1.5-fold and significantly improving regenerative outcomes in IVDD models. Furthermore, encapsulating engineered MSCs in responsive biomaterials establishes a protective niche, ensuring sustained function.
The paradigm is shifting from passive protection to active cellular empowerment. Engineering MSCs with multi-layered, comprehensive ferroptosis shielding is fundamental to unlocking their full therapeutic potential. This engineered cellular empowerment strategy represents a paradigm shift from palliative care to potentially curative, regenerative treatment for IVDD, with the potential to fundamentally change clinical management by addressing the root cause of MSC therapy failure.
椎间盘退变（IVDD）是腰背痛的主要原因，间充质干细胞（MSC）移植是一种很有前景的治疗策略。然而，退变椎间盘的恶劣氧化微环境严重限制了其疗效，这种微环境会迅速引发移植的间充质干细胞发生铁死亡，这是一种铁依赖性的细胞死亡形式。
本综述批判性地评估了当前的铁死亡抑制策略，强调了它们的短暂性或单轴局限性。然后，我们构建了一个分级框架，用于设计强大的间充质干细胞抗性，从双靶点基因回路和遗传-药理学联合，发展到智能、保护性生物材料微环境。
传统方法仅提供部分保护。相比之下，先进的多层策略，包括由遗传-药理学联合（如与TBE56联合）增强的双靶点基因回路（如Prominin-2/FBXO22/BACH1轴），赋予了更好的细胞内在弹性，使间充质干细胞的存活率提高了约1.5倍，并显著改善了IVDD模型中的再生结果。此外，将工程化的间充质干细胞封装在响应性生物材料中可建立一个保护性微环境，确保其持续发挥功能。
范式正在从被动保护转向主动增强细胞能力。设计具有多层、全面铁死亡防护的间充质干细胞对于释放其全部治疗潜力至关重要。这种工程化细胞增强策略代表了从姑息治疗到IVDD潜在治愈性再生治疗的范式转变，有可能通过解决间充质干细胞治疗失败的根本原因从根本上改变临床管理。
