Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis
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 tr...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55929-4 |
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| author | 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 Yi-Fang Li |
| author_facet | 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 Yi-Fang Li |
| author_sort | Qiong-Yi Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-65a3fac7a07c4973bb51250d9c725e62 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-65a3fac7a07c4973bb51250d9c725e622025-01-19T12:30:13ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-025-55929-4Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosisQiong-Yi Zhang0Hai-Biao Gong1Man-Ya Jiang2Fujun Jin3Guan Wang4Chang-Yu Yan5Xiang Luo6Wan-Yang Sun7Shu-Hua Ouyang8Yan-Ping Wu9Wen-Jun Duan10Lei Liang11Yun-Feng Cao12Xin-Xin Sun13Meijing Liu14Gen-Long Jiao15Hua-Jun Wang16Kurihara Hiroshi17Xiaogang Wang18Rong-Rong He19Yi-Fang Li20State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityGuangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical UniversityInnovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityShanghai Institute for Biomedical and Pharmaceutical Technologies, NHC Key Laboratory of Reproduction RegulationJiujiang Maternal and Child Health HospitalGuangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical UniversityThe First Affiliated Hospital of Jinan University, Jinan UniversityThe First Affiliated Hospital of Jinan University, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityGuangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan UniversityAbstract 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.https://doi.org/10.1038/s41467-025-55929-4 |
| spellingShingle | 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 Yi-Fang Li Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis Nature Communications |
| title | Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| title_full | Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| title_fullStr | Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| title_full_unstemmed | Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| title_short | Regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| title_sort | regulation of enzymatic lipid peroxidation in osteoblasts protects against postmenopausal osteoporosis |
| url | https://doi.org/10.1038/s41467-025-55929-4 |
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