1. Academic Validation
  2. 4-Octyl Itaconate Attenuates Postmenopausal Osteoporosis by Inhibiting Ferroptosis and Enhancing Osteogenesis via the Nrf2 Pathway

4-Octyl Itaconate Attenuates Postmenopausal Osteoporosis by Inhibiting Ferroptosis and Enhancing Osteogenesis via the Nrf2 Pathway

  • Inflammation. 2025 Feb 22. doi: 10.1007/s10753-025-02268-7.
You Li # 1 Yang Li # 1 Pengfei Li # 2 Lei Yang 3 Haijun Li 4 5
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China.
  • 2 School of Postgraduate, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China. leiyang@njmu.edu.cn.
  • 4 Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China. 13901436563@139.com.
  • 5 School of Postgraduate, Nanjing University of Chinese Medicine, Nanjing, China. 13901436563@139.com.
  • # Contributed equally.
Abstract

Bone marrow mesenchymal stem cells (BMSCs) play an important role in bone metabolism and tissue repair, and their ability to differentiate into osteoblasts is crucial in the treatment of bone diseases such as postmenopausal osteoporosis (PMOP). However, the function of BMSCs may be affected by Ferroptosis. Ferroptosis is a cell death mode characterized by excess Fe2+ and lipid peroxidation, which significantly affects the survival rate and differentiation ability of BMSCs. This study investigated the effect of exogenous itaconate derivative 4-octyl itaconate (4-OI) on Erastin-induced BMSCs Ferroptosis. The results showed that 4-OI significantly inhibited Erastin-induced BMSCs Ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, reduced Reactive Oxygen Species levels and oxidative damage, and restored antioxidant capacity. At the same time, 4-OI promoted the osteogenic differentiation of BMSCs. Further experiments showed that Nrf2-IN-1, an inhibitor of the Nrf2 pathway, could reverse the protective effect of 4-OI. In vivo, 4-OI was shown to reduce bone loss in ovariectomized (OVX) mice, as assessed by Micro-CT analysis. Immunofluorescence staining further revealed increased GPX4 and Nrf2 expression in vertebral tissues following 4-OI treatment. These results indicate that 4-OI improves Ferroptosis of BMSCs and enhances osteogenic differentiation ability by activating the Nrf2 pathway, providing new research ideas and potential targets for the treatment of PMOP.

Keywords

4-octyl itaconate; Bone Marrow Mesenchymal Stem Cells; Ferroptosis; Osteogenic Differentiation; Postmenopausal Osteoporosis.

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