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Abstract：
Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.
摘要：
骨关节炎（OA）是导致老年人残疾的最常见的退行性关节疾病，由膝关节的功能和结构改变引起的。为了研究是否可以利用代谢驱动因素来促进软骨修复，采用液相色谱-质谱(LC-MS)非靶向代谢组学方法筛选骨关节炎大鼠血清生物标志物.根据相关性分析，已经证明α-酮戊二酸(α-KG)在各种疾病中具有抗氧化和抗炎性质。这些特性使α-KG成为进一步研究OA的主要候选者。实验结果表明,α-KG能显著抑制H2O2诱导的软骨细胞基质降解和凋亡,降低活性氧（ROS）和丙二醛（MDA）的水平，增加超氧化物歧化酶（SOD）和谷胱甘肽（GSH）/谷胱甘肽二硫化物（GSSG）水平，并上调ETV4、SLC7A11和GPX4的表达。进一步的机理研究观察到α-KG，像Ferrostatin-1（Fer-1），能有效缓解Erastin诱导的细胞凋亡和ECM降解。α-KG和Fer-1在mRNA和蛋白质水平上调ETV4、SLC7A11和GPX4，亚铁离子（Fe2+）积累减少，ATDC5细胞线粒体膜电位(MMP)得以保留。在体内,α-KG处理通过激活ETV4/SLC7A11/GPX4通路抑制OA大鼠铁凋亡。因此，这些发现表明α-KG通过ETV4/SLC7A11/GPX4信号通路抑制铁凋亡，从而缓解OA。这些观察结果表明，α-KG具有治疗和预防OA的潜在治疗特性，从而在未来具有潜在的临床应用。
