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Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis

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机构： [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 ChineseMinistry of Education (MOE), Jinan University, Guangzhou 510632, China. [4]Guangdong Province Key Laboratory of PharmacodynamicConstituents of TCMand NewDrugs 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 AffiliatedHospital of Jinan University, Jinan University,Guangzhou 510632,China. [11]The Second Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China. [12]Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510632, China. [13]State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China

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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.© 2025. The Author(s).

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第一作者：

第一作者机构： [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 ChineseMinistry of Education (MOE), Jinan University, Guangzhou 510632, China. [4]Guangdong Province Key Laboratory of PharmacodynamicConstituents of TCMand NewDrugs Research, Jinan University,Guangzhou 510632, China.

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通讯作者：

通讯机构： [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 ChineseMinistry of Education (MOE), Jinan University, Guangzhou 510632, China. [4]Guangdong Province Key Laboratory of PharmacodynamicConstituents of TCMand NewDrugs Research, Jinan University,Guangzhou 510632, China. [10]The Sixth AffiliatedHospital of Jinan University, Jinan University,Guangzhou 510632,China. [11]The Second Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China. [12]Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510632, China. [13]State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China

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