With the increasing aging population in China, the incidence rate of knee osteoarthritis is expected to rise annually. Therefore, we conducted a study to investigate the crucial role of LPCAT3 in osteoarthritis and its underlying mechanisms. We collected samples from normal volunteers (n = 12) and patients with osteoarthritis (n = 12) at our hospital. It was observed that LPCAT3 mRNA expression was reduced and positively correlated with IL-1β mRNA expression in patients with osteoarthritis. In a mouse model, LPCAT3 mRNA and protein expression were found to be suppressed. Furthermore, in an in vitro model, the enrichment level of LPCAT3 mRNA was inhibited by a specific m6A antibody through si-METTL3. Si-METTL3 also reduced the stability of LPCAT3 mRNA in the in vitro model. The inhibition of LPCAT3 was found to exacerbate osteoarthritis in the mouse model. Additionally, LPCAT3 was shown to reduce inflammation in the in vitro model. It was also observed that LPCAT3 reduced chondrocyte ferroptosis by inhibiting mitochondrial damage. LPCAT3 protein was found to interact with ACSL4 protein, and its up-regulation suppressed ACSL4 expression in the in vitro model. ACSL4 was identified as a target of LPCAT3 for suppressing mitochondrial damage in the in vitro model. In conclusion, this study demonstrates that LPCAT3 improves osteoarthritis by regulating ACSL4 to inhibit chondrocyte ferroptosis, thus providing a novel target for the treatment of osteoarthritis.

中文翻译：

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LPCAT3 的甲基化调节通过调节 ACSL4 抑制软骨细胞铁死亡来改善骨关节炎

随着我国人口老龄化的加剧，膝骨关节炎的发病率预计将逐年上升。因此，我们进行了一项研究来探讨LPCAT3在骨关节炎中的关键作用及其潜在机制。我们从我们医院的正常志愿者 ( n = 12) 和骨关节炎患者 ( n = 12) 中收集了样本。结果发现骨关节炎患者LPCAT3 mRNA表达量降低且与IL-1β mRNA表达量呈正相关。在小鼠模型中，LPCAT3 mRNA 和蛋白质表达被发现受到抑制。此外，在体外模型中，LPCAT3 mRNA 的富集水平通过 si-METTL3 被特异性 m6A 抗体抑制。Si-METTL3 还降低了体外模型中 LPCAT3 mRNA 的稳定性。研究发现，抑制 LPCAT3 会加剧小鼠模型中的骨关节炎。此外，LPCAT3 在体外模型中被证明可以减少炎症。还观察到 LPCAT3 通过抑制线粒体损伤来减少软骨细胞铁死亡。LPCAT3 蛋白被发现与 ACSL4 蛋白相互作用，并且其上调在体外模型中抑制 ACSL4 表达。ACSL4 被确定为 LPCAT3 在体外模型中抑制线粒体损伤的靶标。总之，本研究表明LPCAT3通过调节ACSL4抑制软骨细胞铁死亡来改善骨关节炎，从而为骨关节炎的治疗提供新的靶点。