2. Academic Validation
  3. Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

  • Nat Commun. 2025 Jan 17;16(1):758. doi: 10.1038/s41467-025-55929-4.
Qiong-Yi Zhang # 1 2 3 4,  Hai-Biao Gong # 1 2 3 4 5,  Man-Ya Jiang # 1 2 3 4,  Fujun Jin # 6,  Guan Wang 7,  Chang-Yu Yan 1 2 3 4,  Xiang Luo 1 2 3 4,  Wan-Yang Sun 1 2 3 4,  Shu-Hua Ouyang 1 2 3 4,  Yan-Ping Wu 1 2 3 4,  Wen-Jun Duan 1 2 3 4,  Lei Liang 1 2 3 4,  Yun-Feng Cao 8,  Xin-Xin Sun 9,  Meijing Liu 6,  Gen-Long Jiao 5 10,  Hua-Jun Wang 5,  Kurihara Hiroshi 1 2 3 4,  Xiaogang Wang 11,  Rong-Rong He 12 13 14 15 16 17 18 19,  Yi-Fang Li 20 21 22 23 24 25
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China.
  • 2 Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China.
  • 3 International Cooperative Laboratory of TCM Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China.
  • 4 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, China.
  • 5 The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China.
  • 6 Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, PR China.
  • 7 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 8 Shanghai Institute for Biomedical and Pharmaceutical Technologies, NHC Key Laboratory of Reproduction Regulation, Shanghai, 200032, China.
  • 9 Jiujiang Maternal and Child Health Hospital, Jiujiang, 332000, China.
  • 10 The Sixth Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China.
  • 11 Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, PR China. xiaogangwang@smu.edu.cn.
  • 12 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 13 Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 14 International Cooperative Laboratory of TCM Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 15 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 16 The Sixth Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 17 The Second Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 18 Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, 510632, China. rongronghe@jnu.edu.cn.
  • 19 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China. rongronghe@jnu.edu.cn.
  • 20 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • 21 Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • 22 International Cooperative Laboratory of TCM Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • 23 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • 24 The Second Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • 25 Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, 510632, China. liyifang706@jnu.edu.cn.
  • # Contributed equally.
PMID: 39824794 DOI: 10.1038/s41467-025-55929-4
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.

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