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Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

Author

Listed:
  • Qiong-Yi Zhang

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Hai-Biao Gong

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Man-Ya Jiang

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Fujun Jin

    (The Third Affiliated Hospital of Southern Medical University)

  • Guan Wang

    (Sichuan University)

  • Chang-Yu Yan

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Xiang Luo

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Wan-Yang Sun

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Shu-Hua Ouyang

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Yan-Ping Wu

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Wen-Jun Duan

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Lei Liang

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Yun-Feng Cao

    (NHC Key Laboratory of Reproduction Regulation)

  • Xin-Xin Sun

    (Jiujiang Maternal and Child Health Hospital)

  • Meijing Liu

    (The Third Affiliated Hospital of Southern Medical University)

  • Gen-Long Jiao

    (Jinan University
    Jinan University)

  • Hua-Jun Wang

    (Jinan University)

  • Kurihara Hiroshi

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Xiaogang Wang

    (The Third Affiliated Hospital of Southern Medical University)

  • Rong-Rong He

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

  • Yi-Fang Li

    (Jinan University
    Jinan University
    Jinan University
    Jinan University)

Abstract

Oxidative stress plays a critical role in postmenopausal osteoporosis, yet its impact on osteoblasts remains underexplored, limiting therapeutic advances. Our study identifies phospholipid peroxidation in osteoblasts as a key feature of postmenopausal osteoporosis. Estrogen regulates the transcription of glutathione peroxidase 4 (GPX4), an enzyme crucial for reducing phospholipid peroxides in osteoblasts. The deficiency of estrogen reduces GPX4 expression and increases phospholipid peroxidation in osteoblasts. Inhibition or knockout of GPX4 impairs osteoblastogenesis, while the elimination of phospholipid peroxides rescues bone formation and mitigates osteoporosis. Mechanistically, 4-hydroxynonenal, an end-product of phospholipid peroxidation, binds to integrin-linked kinase and triggers its protein degradation, disrupting RUNX2 signaling and inhibiting osteoblastogenesis. Importantly, we identified two natural allosteric activators of GPX4, 6- and 8-Gingerols, which promote osteoblastogenesis and demonstrate anti-osteoporotic effects. Our findings highlight the detrimental role of phospholipid peroxidation in osteoblastogenesis and underscore GPX4 as a promising therapeutic target for osteoporosis treatment.

Suggested Citation

  • Qiong-Yi Zhang & Hai-Biao Gong & Man-Ya Jiang & Fujun Jin & Guan Wang & Chang-Yu Yan & Xiang Luo & Wan-Yang Sun & Shu-Hua Ouyang & Yan-Ping Wu & Wen-Jun Duan & Lei Liang & Yun-Feng Cao & Xin-Xin Sun &, 2025. "Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55929-4
    DOI: 10.1038/s41467-025-55929-4
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    References listed on IDEAS

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    1. Eikan Mishima & Junya Ito & Zijun Wu & Toshitaka Nakamura & Adam Wahida & Sebastian Doll & Wulf Tonnus & Palina Nepachalovich & Elke Eggenhofer & Maceler Aldrovandi & Bernhard Henkelmann & Ken-ichi Ya, 2022. "A non-canonical vitamin K cycle is a potent ferroptosis suppressor," Nature, Nature, vol. 608(7924), pages 778-783, August.
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