Fan Yinuo, Chen Zhiwen, Wang Haixing, Jiang Mengyu, Lu Hongduo, Wei Yangwenxiang, Hu Yunhao, Mo Liang, Liu Yuhao, Zhou Chi, He Wei, Chen Zhenqiu
Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Bone Res. 2025 Jan 26;13(1):18. doi: 10.1038/s41413-024-00390-0.
The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.
糖皮质激素（GC）介导的氧化应激诱导的成骨细胞死亡在类固醇诱导的股骨头坏死（SIONFH）的发展中起关键作用。改善成骨细胞驱动的骨形成在SIONFH的预后方面已显示出有前景的结果。异荭草素已表现出抗氧化特性，但其对GC诱导的氧化应激和SIONFH的治疗作用仍未得到探索。在本研究中，我们使用蛋白质组学和生物信息学方法分析了从SIONFH患者获得的临床样本。我们发现SIONFH中线粒体稳态失衡以及铁死亡诱导的成骨能力受损。随后，我们研究了线粒体与铁死亡之间的因果关系，以及线粒体自噬在维持线粒体稳态和控制铁死亡中的调节作用。然后我们确定了SIRT3在调节线粒体稳态和铁死亡中的关键作用。此外，分子对接和免疫共沉淀证实了SIRT3与BNIP3之间的强相互作用。令人惊讶的是，恢复SIRT3表达显著抑制了由BNIP3/NIX途径介导的病理性线粒体自噬。此外，我们发现异荭草素通过促进SIRT3表达，有效调节线粒体自噬，维持成骨细胞中的线粒体稳态，抑制铁死亡，并恢复成骨能力，从而导致SIONFH有显著改善。这些发现揭示了异荭草素对SIONFH的作用和分子机制，并强调了靶向SIRT3作为一种有前景的策略的潜力，以抑制成骨细胞中线粒体自噬介导的铁死亡并对抗SIONFH。
