Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Rhubarb extract attenuates periodontitis by modulating an MMP3-associated inflammatory-ferroptotic axis: Integrated multi-omics analysis and experimental validation.
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Hou Yifei, Yan Chongzheng, Zhao Hongxu, Yang Zihan, Li Yijing, Lu Xiamei, Yang Aohua, Xu Xinrui, Wu Xinhui, Song Xuan, Zhang Jianing, Liu Yi
Аннотация
BACKGROUND: Periodontitis is a chronic inflammatory disease characterized by dysregulated host immunity, oxidative injury, connective tissue breakdown, and alveolar bone loss. Rhubarb (Rhei Radix et Rhizoma) has anti-inflammatory and redox-modulating properties, but its therapeutic mechanism in periodontitis remains unclear.
PURPOSE: This study investigated whether rhubarb extract alleviates periodontal inflammatory injury and explored the role of matrix metalloproteinase 3 (MMP3) in periodontitis and ferroptosis.
METHODS: The rhubarb extract was profiled by UPLC-Q-TOF-MS. Network pharmacology, transcriptomics, and untargeted metabolomics were integrated to identify targets and pathways. LPS-stimulated human gingival fibroblasts (HGFs), MMP3 knockdown and overexpression, molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), and a rat periodontitis model were used for mechanistic validation.
RESULTS: The rhubarb extract contained anthraquinone derivatives. Integrated multiomics identified MMP3 as a rhubarb-responsive hub linked to inflammatory activation and ferroptosis-related metabolic disruption. Rhubarb extract inhibited LPS-induced NF-κB activation and cytokine production, restored the SLC7A11/GPX4 antioxidant defense axis, and suppressed ACSL4/LPCAT3-associated lipid remodeling. These effects were accompanied by reduced ROS generation, Fe²⁺ accumulation, lipid peroxidation, and mitochondrial damage. MMP3 silencing partially mimicked the anti-ferroptotic effects of rhubarb extract, whereas MMP3 overexpression weakened its cytoprotective activity. Molecular docking, molecular dynamics simulation, and SPR analyses supported direct interactions between representative rhubarb constituents and MMP3. In vivo, rhubarb extract reduced periodontal inflammation, collagen degradation, iron deposition, osteoclast formation, and alveolar bone loss.
CONCLUSION: Rhubarb extract attenuates experimental periodontitis by suppressing inflammation, ferroptosis-related lipid peroxidation, and osteoclast-mediated bone resorption, partly through the modulation of an MMP3-associated inflammatory-ferroptotic axis.
PURPOSE: This study investigated whether rhubarb extract alleviates periodontal inflammatory injury and explored the role of matrix metalloproteinase 3 (MMP3) in periodontitis and ferroptosis.
METHODS: The rhubarb extract was profiled by UPLC-Q-TOF-MS. Network pharmacology, transcriptomics, and untargeted metabolomics were integrated to identify targets and pathways. LPS-stimulated human gingival fibroblasts (HGFs), MMP3 knockdown and overexpression, molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), and a rat periodontitis model were used for mechanistic validation.
RESULTS: The rhubarb extract contained anthraquinone derivatives. Integrated multiomics identified MMP3 as a rhubarb-responsive hub linked to inflammatory activation and ferroptosis-related metabolic disruption. Rhubarb extract inhibited LPS-induced NF-κB activation and cytokine production, restored the SLC7A11/GPX4 antioxidant defense axis, and suppressed ACSL4/LPCAT3-associated lipid remodeling. These effects were accompanied by reduced ROS generation, Fe²⁺ accumulation, lipid peroxidation, and mitochondrial damage. MMP3 silencing partially mimicked the anti-ferroptotic effects of rhubarb extract, whereas MMP3 overexpression weakened its cytoprotective activity. Molecular docking, molecular dynamics simulation, and SPR analyses supported direct interactions between representative rhubarb constituents and MMP3. In vivo, rhubarb extract reduced periodontal inflammation, collagen degradation, iron deposition, osteoclast formation, and alveolar bone loss.
CONCLUSION: Rhubarb extract attenuates experimental periodontitis by suppressing inflammation, ferroptosis-related lipid peroxidation, and osteoclast-mediated bone resorption, partly through the modulation of an MMP3-associated inflammatory-ferroptotic axis.