Gamma-oryzanol alleviates osteoarthritis development by targeting Keap1-Nrf2 binding to interfere with chondrocyte ferroptosis

  • Int Immunopharmacol. 2024 Jan 10:128:111469. doi: 10.1016/j.intimp.2023.111469.
Zi-Han Dai  1 ,  Chen-Cheng Zhou  2 ,  Cai-Yu Yu  2 ,  Cheng-Jie Qian  3 ,  Shu-Qing Jin  2 ,  Shi-Qi Du  2 ,  Yi-Yun Lv  2 ,  Chen Jin  4 ,  Gang Zheng  5 ,  Yu Zhan  6
Affiliations
  • 1. Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, 2# Fuxue Lane, Wenzhou 325000, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • 2. The Second School of Medicine, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
  • 3. Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109# Xueyuan Road, Wenzhou 325000, Zhejiang Province, China.
  • 4. Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109# Xueyuan Road, Wenzhou 325000, Zhejiang Province, China. Electronic address: [email protected].
  • 5. Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109# Xueyuan Road, Wenzhou 325000, Zhejiang Province, China. Electronic address: [email protected].
  • 6. Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, 2# Fuxue Lane, Wenzhou 325000, Zhejiang Province, China. Electronic address: [email protected].
PMID: 38211480 DOI: 10.1016/j.intimp.2023.111469
Abstract

Osteoarthritis (OA) is a prevalent joint disorder pathologically correlated to chondrocyte Ferroptosis. Gamma-oryzanol (γ-Ory), as a first-line drug for autonomic disorders, aroused our interest because of its antioxidant, lipid-lowering, and hypoglycemic potential. The purpose of this study was to investigate the potential impact and mechanism of γ-Ory in treating OA. And the inhibition of γ-Ory in extracellular matrix molecule (ECM) degradation, Ferroptosis, and Keap1-Nrf2 binding in IL-1β-exposed chondrocytes was detected via immunoblotting, immunofluorescence, and co-immunoprecipitation. Micro-CT, SO staining, and immunofluorescence have been conducted to assess the impact of γ-Ory treatment on ACLT-mediated OA in rats at both imaging and histological stages. We found that γ-Ory dose-dependently suppressed IL-1β-induced ECM deterioration and chondrocyte Ferroptosis. Our animal experiments revealed that γ-Ory delayed ACLT-mediated OA development. Mechanistically, γ-Ory interfered with the binding of Keap1 to Nrf2 to promote the latter's nuclear import, thereby increasing the expression of detoxification Enzymes. Summarily, our works support γ-Ory's potential as a candidate drug for the treatment of OA.

Keywords
Chondrocyte; Ferroptosis; Gramma-oryzanol; Nrf2; Osteoarthritis.
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