Didymin halts knee osteoarthritis progression by targeting the GSK3B/5-LOX/11-HETE pathway to suppress chondrocyte ferroptosis.

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Abstract

[Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare no competing interests. 12. Phytomedicine. 2025 Nov 25;148:157431. doi: 10.1016/j.phymed.2025.157431. Epub 2025 Oct 20. Integrative Metabolomics and Pharmacology Reveal Guzhi Zengsheng Zhitongwan's Mechanism in Knee Osteoarthritis. Zhou Y(1), Ng L(2), Chen Z(3), Qin L(4), Xiao P(4), Zhang Q(5), Liu Y(5), Liu C(2), Li X(6), Huang W(7), He R(8). Author information: (1)Postdoctoral Research Workstation, Orthopedic Hospital, Chongqing University of Chinese Medicine, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, Chongqing 400012, China; Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing 400016, China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, China. Electronic address: zyhenry123@163.com. (2)Institute of Orthopaedic and Musculoskeletal Science, University College London, Royal National Orthopaedic Hospital, Stanmore, London HA7 4LP, UK. (3)State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, 999078 Macao, China. (4)Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing 400016, China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, China. (5)Postdoctoral Research Workstation, Orthopedic Hospital, Chongqing University of Chinese Medicine, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, Chongqing 400012, China. (6)Pharmacy Department, Orthopedic Hospital, Chongqing University of Chinese Medicine, Chongqing Orthopedic Hospital of Traditional Chinese Medicine, Chongqing 400012, China. Electronic address: 877139779@qq.com. (7)Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing 400016, China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, China. Electronic address: huangwei123@163.com. (8)College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China. Electronic address: rhe168@126.com. BACKGROUND: Knee osteoarthritis (KOA), a prevalent degenerative disease causing significant disability, currently has no treatments targeting its underlying pathology. Guzhi Zengsheng Zhitongwan (GZZSZTW), a traditional Chinese medicine, appears effective in alleviating KOA symptoms, but its active ingredients and mechanisms are not yet fully understood. PURPOSE: To elucidate the efficacy, safety, and mechanistic basis of GZZSZTW in the treatment of KOA. STUDY DESIGN: An experimental study was conducted to evaluate the efficacy and safety of GZZSZTW in a rat model of KOA. The study integrated metabolomics, pharmacological analysis, and molecular docking (MD) to identify key components and pathways involved in the therapeutic effects of GZZSZTW. METHODS: The KOA model was developed in rats using DMM surgery combined with running. The effectiveness and safety of GZZSZTW were evaluated through gait analysis, micro-CT, ELISA, and serum metabolomics. UPLC-Q-TOF-MSE helped identify chemical components in GZZSZTW and its absorbed prototypes in the serum. Network pharmacology was used to predict targets, build PPI networks, and analyse pathways. MD, MD simulations, IHC, qRT-PCR, and WB tests were subsequently conducted to validate key interactions and targets. RESULTS: GZZSZTW significantly improved gait abnormalities, enhanced bone parameters (such as BMD, BV/TV, and Tb.Th), and lowered pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in KOA rats. Importantly, no hepatorenal toxicity was detected, with serum ALT, AST, creatinine, or urea levels remaining unchanged. Metabolomics showed that GZZSZTW modulated the serum metabolic profile, especially affecting alanine-aspartate-glutamate metabolism. Network pharmacology identified 32 common targets, with topological analysis highlighting seven core targets: SLC2A1, MMP9, MMP2, MPO, HIF1A, CCND1, and ABL1. Pathway analysis pointed to HIF-1 and IL-17 signalling pathways. MD confirmed strong binding affinity (e.g., Paulownin-SLC2A1; Procyanidin C1-MMP9), with stable complexes in MD simulations. Experimental results demonstrated GZZSZTW dose-dependently suppressed the expression of MMP9, MMP2, ABL1, CCND1, MPO, and HIF1A. CONCLUSION: This study shows that GZZSZTW relieves KOA through multiple components, targets, and pathways, mainly by modulating inflammation, remodelling the extracellular matrix, and affecting glucose metabolism via targets include MMP9, MMP2, ABL1, HIF-1A, MPO, CCND1, and SLC2A1. These findings provide a scientific basis for using GZZSZTW in clinical KOA treatment. Copyright © 2025 The Author(s). Published by Elsevier GmbH.. All rights reserved. DOI: 10.1016/j.phymed.2025.157431