Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

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, Meijing Liu, Gen-Long Jiao, Hua-Jun Wang, Kurihara Hiroshi, Xiaogang Wang (), Rong-Rong He () and Yi-Fang Li ()
Additional contact information
Qiong-Yi Zhang: Jinan University
Hai-Biao Gong: Jinan University
Man-Ya Jiang: Jinan University
Fujun Jin: The Third Affiliated Hospital of Southern Medical University
Guan Wang: Sichuan University
Chang-Yu Yan: Jinan University
Xiang Luo: Jinan University
Wan-Yang Sun: Jinan University
Shu-Hua Ouyang: Jinan University
Yan-Ping Wu: Jinan University
Wen-Jun Duan: Jinan University
Lei Liang: 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
Hua-Jun Wang: Jinan University
Kurihara Hiroshi: Jinan University
Xiaogang Wang: The Third Affiliated Hospital of Southern Medical University
Rong-Rong He: Jinan University
Yi-Fang Li: Jinan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55929-4

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