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| 铜死亡基因FDX1与骨关节炎软骨梯度退变的线粒体代谢及免疫微环境相关性分析 |
| Correlation analysis of cuproptosis-related gene FDX1 with mitochondrial metabolism and immune microenvironment in gradient cartilage degeneration of osteoarthritis |
| 投稿时间：2026-06-15 修订日期：2026-09-12 |
| DOI： |
| 中文关键词: 骨关节炎 FDX1 铜死亡 线粒体 转录组分析 软骨退变 免疫浸润 |
| 英文关键词: Osteoarthritis FDX1 Cuproptosis Mitochondria Transcriptome analysis Cartilage degeneration Immune infiltration |
| 基金项目:济宁市重点研发计划(2025YXNS027) |
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| 中文摘要: |
| 目的 骨关节炎是导致人残疾的主要关节疾病，软骨细胞线粒体代谢失衡与局部免疫微环境紊乱是其核心病理特征，但介导二者串扰的关键分子机制尚未明确。铜死亡是一种依赖铜离子蓄积、由线粒体三羧酸循环介导的新型程序性细胞死亡，铁氧还蛋白 1（Ferredoxin 1, FDX1）为该通路的核心调控因子，但其在骨关节炎梯度软骨退变进程中的表达变化与调控作用仍待阐明。本研究旨在探讨FDX1相关的铜死亡通路在骨关节炎发生发展中的表达特征及潜在关联。
方法 本研究基于GEO数据库GSE57218转录组数据集，纳入健康软骨（Healthy）、退变保留区软骨（Preserved）及骨关节炎病变软骨（OA）三组样本；通过差异表达分析筛选铜死亡核心基因在软骨退变不同阶段的表达特征；采用单样本基因集富集分析（ssGSEA）计算铜死亡通路富集评分，评估通路整体活性；通过基因集富集分析（GSEA）解析FDX1相关的线粒体能量代谢通路；利用ssGSEA算法量化27种免疫细胞浸润丰度，分析FDX1表达与关节免疫微环境的相关性。
结果 与健康软骨相比，退变保留区与骨关节炎病变软骨中FDX1、LIPT1、MTF1等铜死亡相关基因表达均显著下调；铜死亡通路活性在退变保留区即显著降低，并在病变阶段持续维持低水平。GSEA分析显示，FDX1表达水平与ATP合成、线粒体ATP合成等多条能量代谢通路呈显著负相关，即FDX1低表达对应线粒体能量代谢通路异常激活。免疫浸润结果表明，FDX1低表达组中活化CD4?/CD8? T细胞、自然杀伤细胞等多种促炎免疫细胞浸润丰度显著升高，记忆B细胞浸润水平显著降低。
结论 本研究首次在OA梯度退变软骨中揭示FDX1相关铜死亡通路与线粒体代谢重编程及免疫微环境紊乱的关联，为骨关节炎发病机制研究提供了新视角；FDX1有望成为骨关节炎的潜在候选生物标志物，靶向铜死亡通路也为该病的防治提供了新的研究方向。 |
| 英文摘要: |
| Objective Osteoarthritis is a major joint disease causing disability. Mitochondrial metabolic imbalance in chondrocytes and disturbance of the local immune microenvironment represent its core pathological features, yet the key molecular mechanism mediating their crosstalk remains unclear. Cuproptosis is a novel type of programmed cell death dependent on copper accumulation and mediated by the mitochondrial tricarboxylic acid cycle. Ferredoxin 1 (FDX1) acts as a core regulator of this pathway. However, its expression changes and roles during gradient cartilage degeneration in osteoarthritis remain poorly defined. This study aimed to explore the expression characteristics and potential associations of the FDX1-related cuproptosis pathway in the initiation and progression of osteoarthritis.
Methods Based on the transcriptomic dataset GSE57218 from the GEO database, three groups of samples were included: healthy cartilage, preserved cartilage in degenerative regions, and osteoarthritic lesional cartilage. Differential expression analysis was performed to characterize the expression patterns of core cuproptosis genes across different stages of cartilage degeneration. Single-sample gene set enrichment analysis (ssGSEA) was applied to calculate cuproptosis pathway enrichment scores for evaluating overall pathway activity. Gene set enrichment analysis (GSEA) was used to identify mitochondrial energy metabolism pathways associated with FDX1. The ssGSEA algorithm was utilized to quantify the infiltration abundance of 27 immune cell subsets and analyze the correlation between FDX1 expression and the articular immune microenvironment.
Results Compared with healthy cartilage, the expression of cuproptosis-related genes including FDX1, LIPT1 and MTF1 was significantly downregulated in preserved degenerative cartilage and osteoarthritic lesional cartilage. Cuproptosis pathway activity decreased significantly at the preserved degenerative stage and remained low in the lesional stage. GSEA demonstrated that FDX1 expression was significantly negatively correlated with multiple energy metabolism pathways such as ATP synthesis and mitochondrial ATP synthesis, indicating that low FDX1 expression corresponded to aberrant activation of mitochondrial energy metabolism pathways. Immune infiltration analysis revealed that the infiltration abundance of multiple pro-inflammatory immune cells (activated CD4?/CD8? T cells, natural killer cells, etc.) was markedly elevated in the FDX1 low-expression group, while the infiltration level of memory B cells was significantly reduced.
Conclusions This study for the first time identifies the association between the FDX1-related cuproptosis pathway and mitochondrial metabolic reprogramming as well as immune microenvironment disturbance in gradient degenerative OA cartilage, providing new insights into the pathogenesis of osteoarthritis. FDX1 may serve as a potential candidate biomarker for osteoarthritis, and targeting the cuproptosis pathway offers a new research direction for the prevention and treatment of this disease. |
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