Nuciferine ameliorates steroid-induced osteonecrosis of the femoral head by inhibiting BMSCs ferroptosis via HIF-1α

  • Phytomedicine. 2026 Jun:155:158070. doi: 10.1016/j.phymed.2026.158070.
Weiqian Sun  1 ,  Jing Wang  2 ,  Tanxin Yu  3 ,  Shaohan Xu  4 ,  Dexin Lin  5 ,  Qi Zhuang  6 ,  Yufeng Tang  7 ,  Changquan Liu  8 ,  Xiaolei Zhang  9 ,  Huachen Yu  10
Affiliations
  • 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 2. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 3. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 4. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 5. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 6. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 7. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 8. Department of Orthopedics, Shenzhen Second People's Hospital, Shenzhen 518035, Guangdong, China; Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, Guangdong, China. Electronic address: [email protected].
  • 9. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
  • 10. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325003, China. Electronic address: [email protected].
PMID: 41861683 DOI: 10.1016/j.phymed.2026.158070
Abstract

Objective: Glucocorticoid use is a leading cause of osteonecrosis of the femoral head, with the death of bone marrow mesenchymal stem cells (BMSCs) considered a central cellular event in steroid-induced osteonecrosis of the femoral head (SONFH). However, the underlying mechanisms remain unclear, and effective therapies are lacking.

Method: In this study, we established an in vitro model of SONFH by treating BMSCs with methylprednisolone (MP, 1 mM, 24 h) and screened a natural product library for inhibitors of the steroid-induced cell death (SiCD).

Results: Our results demonstrated that 15 natural products may effectively inhibit SiCD among the screened library, with nuciferine emerging as one of the most potent compounds. Further study showed that nuciferine may predominantly suppress Ferroptosis in glucocorticoid treated BMSCs, it may also promote osteogenic differentiation and mitochondrial homeostasis. Mechanistically, integrated bioinformatic analysis and gene knockdown experiments revealed that nuciferine relies on HIF-1α to inhibit Ferroptosis and promote osteogenic differentiation. In vivo studies showed that administration of nuciferine effectively ameliorates SONFH in rats.

Conclusions: In summary, our study demonstrates that nuciferine may ameliorate SONFH by activating HIF-1α to suppress Ferroptosis in BMSCs. Given that nuciferine is both a medicinal and dietary compound, it may also suggest that nuciferine could be a key dietary component for patients undergoing glucocorticoid treatment.

Keywords
Bone marrow stem cells; Ferroptosis; Glucocorticoids; Natural product library; Nuciferine; ONFH.
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