Homocysteine (Hcy) is an amino acid involved in gene methylation. Plasma concentration of Hcy is elevated in the pathological condition hyperhomocysteinemia (HHcy), which increases the risk of disorders of the vascular, nervous and musculoskeletal systems, including chondrocyte dysfunction. The present study aimed to explore the role of Hcy in intervertebral disc degeneration (IVDD), using a range of techniques. A clinical epidemiological study showed that HHcy is an independent risk factor for human IVDD. Cell culture using rat nucleus pulposus cells showed that Hcy promotes a degenerative cell phenotype (involving increased oxidative stress and cell death by ferroptosis) which is mediated by upregulated methylation of GPX4. An in-vivo mouse ‘puncture’ model of IVDD showed that folic acid (which is used to treat HHcy in humans) reduced the ability of diet-induced HHcy to promote IVDD. We conclude that Hcy upregulates oxidative stress and ferroptosis in the nucleus pulposus via enhancing GPX4 methylation, and is a new contributing factor in IVDD.

同型半胱氨酸（Hcy）是一种参与基因甲基化的氨基酸。在高同型半胱氨酸血症（HHcy）病理状态下，血浆Hcy浓度升高，这增加了血管，神经和肌肉骨骼系统疾病（包括软骨细胞功能障碍）的风险。本研究旨在探索Hcy在多种椎间盘退变（IVDD）中的作用。临床流行病学研究表明，HHcy是人类IVDD的独立危险因素。使用大鼠髓核细胞进行的细胞培养表明，Hcy促进了退化的细胞表型（涉及氧化应激的增加和由肥大病引起的细胞死亡），这是由GPX4甲基化上调介导的。IVDD的体内小鼠“穿刺”模型显示，叶酸（用于治疗人类的HHcy）降低了饮食诱导的HHcy促进IVDD的能力。我们得出的结论是，Hcy通过增强GPX4甲基化上调髓核中的氧化应激和铁作用，并且是IVDD的新促成因素。