Transferrin receptor-1 (TfR1) plays important roles in controlling cellular iron levels, but its role in OA pathology is unknown. Herein we aim to investigate the role of TfR1 in OA progression and its underlying mechanisms. TfR1 expression in cartilage during OA development were examined both in vivo and in vitro. Then IL-1β was used to induce chondrocytes degeneration in vitro and TfR1 siRNA was used for observing the effect of TfR1 in modulating iron homeostasis, mitochondrial function and degrading enzymes expression. Also the inhibitor of TfR1 was exploited to analyze the protective effect of TfR1 inhibition in vivo. TfR1 is elevated in OA cartilage and contributes to OA inflammation condition. Excess iron not only results in oxidative stress damage and sensitizes chondrocytes to ferroptosis, but also triggers c-GAS/STING-mediated inflammation by promoting mitochondrial destruction and the release of mtDNA. Silencing TfR1 using TfR1 siRNA not only reduced iron content in chondrocytes and inhibited oxidative stress, but also facilitated the mitophagy process and suppressed mtDNA/cGAS/STING-mediated inflammation. Importantly, we also found that Ferstatin II, a novel and selective TfR1 inhibitor, could substantially suppress TfR1 activity both in vivo and in vitro and ameliorated cartilage degeneration. Our work demonstrates that TfR1 mediated iron influx plays important roles in chondrocytes degeneration and OA pathogenesis, suggesting that maintaining iron homeostasis through the targeting of TfR1 may represent a novel therapeutic strategy for the treatment of OA.

中文翻译：

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TfR1介导的铁代谢功能障碍作为骨关节炎的潜在治疗靶点

转铁蛋白受体 1 (TfR1) 在控制细胞铁水平方面发挥着重要作用，但其在 OA 病理学中的作用尚不清楚。在此，我们旨在研究 TfR1 在 OA 进展中的作用及其潜在机制。在体内和体外检查了 OA 发育过程中软骨中 TfR1 的表达。然后使用IL-1β体外诱导软骨细胞变性，并使用TfR1 siRNA观察TfR1调节铁稳态、线粒体功能和降解酶表达的作用。还利用TfR1抑制剂来分析TfR1抑制的体内保护作用。TfR1 在 OA 软骨中升高，导致 OA 炎症。过量的铁不仅会导致氧化应激损伤并使软骨细胞对铁死亡敏感，还会通过促进线粒体破坏和 mtDNA 释放来引发 c-GAS/STING 介导的炎症。使用TfR1 siRNA沉默TfR1不仅可以降低软骨细胞中的铁含量并抑制氧化应激，而且还可以促进线粒体自噬过程并抑制mtDNA/cGAS/STING介导的炎症。重要的是，我们还发现 Ferstatin II 是一种新型选择性 TfR1 抑制剂，可以在体内和体外显着抑制 TfR1 活性，并改善软骨退化。我们的工作表明，TfR1 介导的铁流入在软骨细胞变性和 OA 发病机制中发挥重要作用，表明通过靶向 TfR1 维持铁稳态可能代表治疗 OA 的一种新的治疗策略。