Qiu Cheng, Cheng Lin, Di Derun, Xiang Ziqian, Wang Congyu, Li Jinghang, Xiong Yinuo, Li Manyu, Liu Jingwei, Zhou Jian, Liu Tianyi, Wang Xinyu, Luo Dan, Wang Xiaoxiong, Li Shangye, Wang Hui, Wang Xia, Zhao Yunpeng, Liu Xinyu, Wang Lianlei
Department of Orthopaedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Genes Dis. 2024 Feb 28;12(1):101251. doi: 10.1016/j.gendis.2024.101251. eCollection 2025 Jan.
Intervertebral disc degeneration (IDD) is a common chronic inflammatory degenerative disease that causes lower back pain. However, the underlying mechanisms of IDD remain unclear. Ferroptosis suppressor protein 1 (FSP1) is a newly identified suppressor for ferroptosis. This study aims to investigate the role of FSP1 in IDD. Nucleus pulposus (NP) tissues in humans were collected and NP cells from rats were isolated to detect FSP1 expression pattern. The relationship between FSP1-mediated ferroptosis and apoptosis was identified using FSP1 inhibitor iFSP1. RNA sequencing was utilized to seek downstream molecules and related signaling pathways. Moreover, both exogenous recombinant FSP1 protein and endogenous small interfering RNA were implemented in this study to clarify the role of FSP1 in tumor necrosis factor-alpha (TNFα)-mediated NP cell apoptosis. Ultimately, the underlying mechanisms of FSP1-related signaling pathway in IDD were uncovered both and . As a result, FSP1 was up-regulated in human degenerative NP tissues and after TNFα stimulation. FSP1 inhibition by iFSP1 fails to trigger ferroptosis in NP cells while inhibiting TNFα-mediated apoptosis. Further experiments demonstrated that FSP1 was closely related to TNFα-reliant caspase 3 activation and mitochondrial damage. However, the exogenous addition of recombinant protein FSP1 does not induce cell death or intensify the efficacy of TNFα. Mechanically, FSP1 is involved in TNFα-mediated NF-κB signaling activation to accelerate the development of IDD. This study demonstrated that FSP1 promotes IDD through TNFα-reliant NF-κB signaling activation and caspase 3-dependent apoptosis. These findings suggested a novel therapeutic target for the treatment of IDD.
椎间盘退变（IDD）是一种常见的慢性炎症性退行性疾病，可导致下背部疼痛。然而，IDD的潜在机制仍不清楚。铁死亡抑制蛋白1（FSP1）是一种新发现的铁死亡抑制因子。本研究旨在探讨FSP1在IDD中的作用。收集人类髓核（NP）组织并分离大鼠NP细胞以检测FSP1表达模式。使用FSP1抑制剂iFSP1确定FSP1介导的铁死亡与凋亡之间的关系。利用RNA测序寻找下游分子和相关信号通路。此外，本研究还采用了外源性重组FSP1蛋白和内源性小干扰RNA来阐明FSP1在肿瘤坏死因子-α（TNFα）介导的NP细胞凋亡中的作用。最终，揭示了FSP1相关信号通路在IDD中的潜在机制。结果显示，FSP1在人类退变的NP组织中以及TNFα刺激后上调。iFSP1抑制FSP1未能在NP细胞中触发铁死亡，同时抑制TNFα介导的凋亡。进一步实验表明，FSP1与TNFα依赖的半胱天冬酶3激活和线粒体损伤密切相关。然而，外源性添加重组蛋白FSP1不会诱导细胞死亡或增强TNFα的作用效果。机制上，FSP1参与TNFα介导的NF-κB信号激活，以加速IDD的发展。本研究表明，FSP1通过TNFα依赖的NF-κB信号激活和半胱天冬酶3依赖性凋亡促进IDD。这些发现为IDD的治疗提出了一个新的治疗靶点。
