Zhao Y, Feng XZ, Cao WQ, Chen YR, Yang Y, Liu JC, Xu A, Ren YL, Wang ZM. Zuo Gui pill alleviates M1 macrophage polarization in type 2 diabetic osteoporosis through the Nrf2/HO-1/XCT/GPX4 pathway. World J Diabetes 2026; 17(5): 117635 [DOI: 10.4239/wjd.v17.i5.117635]
Corresponding Author of This Article
Yan-Ling Ren, Professor, Liaoning University of Traditional Chinese Medicine Affiliated Hospital, No. 79 Chongshandong Road, Shenyang 110847, Liaoning Province, China. lnutcmren@163.com
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May 15, 2026 (publication date) through May 14, 2026
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World Journal of Diabetes
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Zhao Y, Feng XZ, Cao WQ, Chen YR, Yang Y, Liu JC, Xu A, Ren YL, Wang ZM. Zuo Gui pill alleviates M1 macrophage polarization in type 2 diabetic osteoporosis through the Nrf2/HO-1/XCT/GPX4 pathway. World J Diabetes 2026; 17(5): 117635 [DOI: 10.4239/wjd.v17.i5.117635]
World J Diabetes. May 15, 2026; 17(5): 117635 Published online May 15, 2026. doi: 10.4239/wjd.v17.i5.117635
Zuo Gui pill alleviates M1 macrophage polarization in type 2 diabetic osteoporosis through the Nrf2/HO-1/XCT/GPX4 pathway
Yi Zhao, Xiu-Zhi Feng, Wen-Qi Cao, Yi-Ran Chen, Ying Yang, Jing-Chi Liu, Ao Xu, Yan-Ling Ren, Zhi-Min Wang
Yi Zhao, Xiu-Zhi Feng, Wen-Qi Cao, Yi-Ran Chen, Ying Yang, Jing-Chi Liu, Ao Xu, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, Liaoning Province, China
Yan-Ling Ren, Zhi-Min Wang, Liaoning University of Traditional Chinese Medicine Affiliated Hospital, Shenyang 110847, Liaoning Province, China
Co-first authors: Yi Zhao and Xiu-Zhi Feng.
Co-corresponding authors: Yan-Ling Ren and Zhi-Min Wang.
Author contributions: Zhao Y and Feng XZ contributed equally to this study and were involved in conceptualization, methodology, data curation, visualization, and writing the original draft as co-first authors; Cao WQ, Chen YR, Yang Y, Liu JC, and Xu A contributed to validation and formal analysis; Ren YL and Wang ZM were involved in reviewing and editing, resources, supervision, funding acquisition, and project administration as co-corresponding authors; All authors read and approved the final version of the manuscript to be published.
Supported by National Natural Science Foundation of China, No. 82174260; and Liaoning Provincial Department of Science and Technology Joint Fund for Doctoral Research Initiation Project, No. 2023-BSBA-224.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals [Liaoning Academy of Traditional Chinese Medicine (No. LZYY240404)].
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Yan-Ling Ren, Professor, Liaoning University of Traditional Chinese Medicine Affiliated Hospital, No. 79 Chongshandong Road, Shenyang 110847, Liaoning Province, China. lnutcmren@163.com
Received: December 16, 2025 Revised: January 8, 2026 Accepted: February 24, 2026 Published online: May 15, 2026 Processing time: 150 Days and 20 Hours
Abstract
BACKGROUND
Zuo Gui pill (ZGP) is a traditional Chinese herbal formula originating from Jing Yue Quan Shu, a medical text from China’s Ming Dynasty. It is commonly administered to cure osteoporosis, stroke, and ovarian aging-related disorders. However, the research on the molecular mechanisms and regulatory pathways of type 2 diabetic osteoporosis (T2DOP) is limited.
AIM
To explore the effects and underlying mechanisms of ZGP in alleviating oxidative damage and inflammatory responses in T2DOP.
METHODS
Network pharmacology was applied to screen the active components of ZGP, followed by pathway enrichment analysis to identify potential therapeutic targets. A T2DOP rat model was established to evaluate the therapeutic effect of ZGP in T2DOP and observe the levels of oxidative damage, inflammatory response, protein and gene expression levels of nuclear factor E2-related factor 2 (Nrf2), hemoxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and XCT in bone tissue as well as M1 macrophage expression in both the ZGP treatment group and the ZGP + Fer-1 synergistic group.
RESULTS
A total of 76 active compounds were identified in ZGP. Pathway enrichment analysis showed that the treatment of T2DOP is linked to the Nrf2 signaling pathway. Animal studies showed that compared with the model group the ZGP group and ZGP + Fer-1 group showed no significant decrease in blood glucose but significant reductions in total cholesterol, triglycerides, and low-density lipoprotein cholesterol (P < 0.001). Bone microstructure parameters showed significant improvement in the ZGP group compared with the model group (P < 0.001). Antioxidant molecule levels and serum inflammatory cytokine levels were markedly decreased (P < 0.001). The protein and gene expression of Nrf2, HO-1, GPX4, and XCT were significantly higher (P < 0.05). Bone marrow macrophage M1 cells in bone tissue were markedly lower (P < 0.05). Cotreatment with ZGP and Fer-1 was associated with restoration of the Nrf2/HO-1/XCT/GPX4 axis and attenuation of oxidative stress and ferroptosis-related changes, accompanied by reduced inflammatory responses and decreased M1 macrophage polarization.
CONCLUSION
ZGP activated the Nrf2/HO-1/XCT/GPX4 signaling pathway to inhibit bone marrow macrophage M1 polarization, effectively preventing and treating T2DOP.
Core Tip: Regulation of M1 polarization of bone marrow macrophages in type 2 diabetic osteoporosis is dependent on the activation of the nuclear factor E2-related factor 2/hemoxygenase-1/XCT/glutathione peroxidase 4 signaling pathway. Zuo Gui pill, metformin, and Fer-1 can work synergistically to restore nuclear factor E2-related factor 2, upregulate hemoxygenase-1, and inhibit M1 polarization of bone marrow macrophages.
