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.

中文翻译：

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TNFα依赖性 FSP1 上调通过 caspase 3 依赖性细胞凋亡促进椎间盘退变

椎间盘退变（IDD）是一种常见的慢性炎症退行性疾病，会导致腰痛。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剂。本研究旨在探讨 FSP1 在 IDD 中的作用。收集人体髓核（NP）组织并分离大鼠髓核（NP）细胞以检测FSP1表达模式。使用 FSP1 抑制剂 iFSP1 确定了 FSP1 介导的铁死亡和细胞凋亡之间的关系。RNA测序用于寻找下游分子和相关信号通路。此外，本研究还采用外源重组FSP1蛋白和内源小干扰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，IDD 中 FSP1 相关信号通路的潜在机制被揭示。结果，FSP1 在人类退行性 NP 组织中以及在 TNFα 刺激后上调。iFSP1 抑制 FSP1 无法引发 NP 细胞的铁死亡，同时抑制 TNFα 介导的细胞凋亡。进一步的实验表明，FSP1与TNFα依赖的caspase 3激活和线粒体损伤密切相关。然而，外源添加重组蛋白 FSP1 不会诱导细胞死亡或增强 TNFα 的功效。从机制上来说，FSP1 参与 TNFα 介导的 NF-κB 信号传导激活，从而加速 IDD 的发展。这项研究表明，FSP1 通过 TNFα 依赖的 NF-κB 信号激活和 caspase 3 依赖的细胞凋亡来促进 IDD。这些发现为治疗 IDD 提出了一个新的治疗靶点。