3,4-Dimethoxychalcone Protects Against Steroid Induced Femoral Head Necrosis by Suppressing Ferroptosis via Activation of STAT3-Nrf2 Signaling Pathway

  • FASEB J. 2026 Jun 30;40(12):e72021. doi: 10.1096/fj.202600307R.
Li-Jiang Han  1  2 ,  Jian-Sen Miao  1  2 ,  Sheng-Huan Wu  3 ,  Juan-Nan Zhan  1  2 ,  Guang-Can Tan  1  2 ,  Jian-Feng Yang  1  2 ,  Lian-Wei Zhang  1  2 ,  Zheng-Hao Wu  1  2 ,  Le-Yang Liu  1  2 ,  Ping Shang  4 ,  Cheng-Long Xie  1  2 ,  Hai-Xiao Liu  1  2
Affiliations
  • 1. Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China.
  • 3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 4. Department of Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
PMID: 42268673 DOI: 10.1096/fj.202600307R
Abstract

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently encountered complication in orthopedic practice, yet its precise pathogenic mechanisms remain incompletely understood. Dysregulation of bone metabolism induced by glucocorticoids (GCs) is considered a key contributing factor. 3,4-Dimethoxychalcone (3,4DC), an organic compound, has shown potential biological activities, but its role in the context of GIONFH has not been elucidated. This study investigates the protective effects and underlying mechanisms of 3,4DC against dexamethasone (Dex)-induced Ferroptosis and its therapeutic potential in GIONFH.A rat model of GIONFH was established through intraperitoneal administration of Dex, and in vitro studies were performed by culturing osteoblasts (OBs) under Dex treatment conditions. To evaluate the effects of 3,4DC on Dex-treated OBs, we employed C11-BODIPY and FerroOrange staining, assessed mitochondrial function, and analyzed protein expression via Western blot and immunofluorescence. The impact of 3,4DC on the bone microarchitecture of the femoral head in rats was further examined using micro-CT, H&E staining, as well as immunofluorescence and immunohistochemistry at both imaging and histological levels. Our results indicate that 3,4DC effectively inhibits Dex-induced Ferroptosis and attenuates the development of GIONFH. In vitro, 3,4DC treatment significantly increased glutathione (GSH) levels while reducing malondialdehyde (MDA) production, lipid peroxidation, and mitochondrial Reactive Oxygen Species (ROS) accumulation. Furthermore, 3,4DC enhanced STAT3 phosphorylation, upregulated Glutathione Peroxidase 4 (GPX4) and osteogenesis-related proteins, and promoted bone formation. Mechanistically, 3,4DC activated the STAT3/Nrf2 signaling pathway. Notably, silencing STAT3 with siRNA abrogated the protective effects of 3,4DC in Dex-treated OBs.3,4DC alleviates GIONFH by activating the STAT3/Nrf2 signaling pathway, thereby suppressing Ferroptosis and may have potential clinical applications.

Keywords
3,4‐dimethoxychalcone; GIONFH; STAT3‐Nrf2 signaling pathway; ferroptosis; osteoblast.
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