Iron overload enhances osteoclastic bone resorption and induces osteoporosis. Excess iron is highly toxic. The modulation of redox and iron homeostasis is critical for osteoclast differentiation under iron-overload condition. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against oxidative stress and iron overload through the expression of genes involved in anti-oxidative processes and iron metabolism. Our studies demonstrated that NRF2 activation was suppressed during osteoclast differentiation. Under iron-overload condition, NRF2 and its mediated antioxidant and iron metabolism genes were activated by reactive oxygen species (ROS), which enhanced antioxidant capability. NRF2 mediated the upregulation of iron exporter ferroportin 1 (FPN1) and iron storage protein ferritin, contributing to decreased levels of intracellular iron. Nfe2l2 knockout induced oxidative stress and promoted osteoclast differentiation under normal condition, but induced ferroptosis under iron-overload condition. Nfe2l2 knockout alleviated iron overload induced bone loss by inhibiting osteoclast differentiation. Our results suggest that NRF2 activation is essential for osteoclast differentiation by enhancing antioxidant capability and reducing intracellular iron under iron-overload condition. Targeting NRF2 to induce ferroptosis could be a potential therapy for the treatment of iron-overload induced osteoporosis.

铁超载会增强破骨细胞的骨吸收并诱发骨质疏松。过量的铁具有剧毒。氧化还原和铁稳态的调节对于铁过载条件下的破骨细胞分化至关重要。核因子红细胞 2 相关因子 2 (NRF2) 是一种转录因子，通过表达参与抗氧化过程和铁代谢的基因来调节细胞防御氧化应激和铁过载的能力。我们的研究表明，NRF2 激活在破骨细胞分化过程中受到抑制。在铁过载条件下，NRF2及其介导的抗氧化和铁代谢基因被活性氧（ROS）激活，从而增强了抗氧化能力。 NRF2 介导铁输出蛋白铁转运蛋白 1 (FPN1) 和铁储存蛋白铁蛋白的上调，导致细胞内铁水平下降。 Nfe2l2敲除在正常条件下诱导氧化应激并促进破骨细胞分化，但在铁过载条件下诱导铁死亡。 Nfe2l2敲除通过抑制破骨细胞分化减轻铁过载引起的骨质流失。我们的结果表明，NRF2 激活通过增强抗氧化能力和在铁过载条件下减少细胞内铁，对于破骨细胞分化至关重要。靶向 NRF2 诱导铁死亡可能是治疗铁过载引起的骨质疏松症的潜在疗法。