2. Academic Validation
  3. Targeting SIRT3 to regulate mitophagy-dependent ferroptosis for preventing glucocorticoid-induced osteoporosis

Targeting SIRT3 to regulate mitophagy-dependent ferroptosis for preventing glucocorticoid-induced osteoporosis

  • Int J Surg. 2025 Jul 2. doi: 10.1097/JS9.0000000000002783.
Yunhao Hu 1 2 3,  Hongduo Lu 1 2,  Hanjun Fang 3,  Benlu Chen 1 2 3,  Zhiwen Chen 1 2 3,  Mengyu Jiang 1 2 3,  Yuehui Zhou 1 2 3,  Ziyuan Li 1 3,  Shihua Gao 4,  Zeqing Huang 3,  Chi Zhou 3,  Yuhao Liu 3,  Zhenqiu Chen 3 5,  Yinuo Fan 3
Affiliations

Affiliations

  • 1 Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 2 The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3 The Department of Orthopedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China.
  • 4 Department of Orthopaedics, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong, China.
  • 5 State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, Guangdong Province, China.
PMID: 40607908 DOI: 10.1097/JS9.0000000000002783
Abstract

Background: Compelling evidence has implicated osteoblast Ferroptosis as a critical contributor to the pathogenesis of (GIOP), However, the underlying regulatory mechanisms remain poorly understood.

Methods: In the glucocorticoids (GCs)-induced GIOP rat model, both osteoblast dysfunction and Ferroptosis markers were assessed. Ferroptosis was inhibited with deferoxamine (DFO). Transcriptomic profiling was performed to analyze the correlation between Mitophagy and SIRT3 levels. In MC3T3-E1 cells exposed to GCs, we examined key Mitophagy markers PINK1 and PARKIN, mitochondrial function, and SIRT3 expression. Treatments included DFO, Mitophagy inhibitors (Mdivi-1), and SIRT3 agonists (Nicotinamide riboside chloride).

Results: In the GIOP rat model, significant osteoblast dysfunction and elevated Ferroptosis markers were observed. Although DFO treatment inhibited Ferroptosis, it failed to restore osteogenesis, suggesting the involvement of additional regulatory mechanisms in osteogenic function regulation. Transcriptomic profiling highlighted a robust correlation between Mitophagy and SIRT3 levels in glucocorticoid-induced osteoporosis (GIOP). In GC-exposed MC3T3-E1 cells, key Mitophagy markers PINK1 and PARKIN were upregulated, mitochondrial function was impaired, and SIRT3 expression was significantly reduced. Notably, while DFO treatment did not restore mitochondrial homeostasis, the application of Mdivi-1 (Mitophagy inhibitor) and Nicotinamide riboside chloride (SIRT3 agonists) effectively alleviated Ferroptosis and restored mitochondrial function.

Conclusions: SIRT3 regulates Ferroptosis by inhibiting excessive Mitophagy in osteoblasts, providing a novel mechanistic pathway for mitigating GIOP. These findings suggest that SIRT3 represents a critical regulator of mitophagy-dependent Ferroptosis and a potential therapeutic target for GIOP.

Keywords

SIRT3; ferroptosis; glucocorticoid-induced osteoporosis; mitophagy.

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