大黄提取物通过调节MMP3相关的炎性铁下垂轴来减轻牙周炎：综合多组学分析和实验验证
Rhubarb extract attenuates periodontitis by modulating an MMP3-associated inflammatory-ferroptotic axis: Integrated multi-omics analysis and experimental validation.
摘要(中文译文)
牙周炎是一种以宿主免疫失调、氧化损伤、结缔组织破坏和牙槽骨丧失为特征的慢性炎症性疾病。大黄（Rhei Radix et Rhizoma）具有抗炎和氧化还原调节特性，但其在牙周炎中的治疗机制尚不清楚。本研究探讨大黄提取物是否减轻牙周炎症损伤，并探究基质金属蛋白酶3（MMP3）在牙周炎和铁死亡中的作用。采用UPLC-Q-TOF-MS对大黄提取物进行成分分析。整合网络药理学、转录组学和非靶向代谢组学以识别靶点和通路。采用LPS刺激的人牙龈成纤维细胞（HGFs）、MMP3敲低和过表达、分子对接、分子动力学模拟、表面等离子体共振（SPR）以及大鼠牙周炎模型进行机制验证。大黄提取物含有蒽醌衍生物。整合多组学鉴定MMP3为大黄响应性枢纽靶点，与炎症激活和铁死亡相关代谢紊乱有关。大黄提取物抑制LPS诱导的NF-κB激活和细胞因子产生，恢复SLC7A11/GPX4抗氧化防御轴，并抑制ACSL4/LPCAT3相关的脂质重塑。这些效应伴随ROS生成、Fe²⁺蓄积、脂质过氧化和线粒体损伤的减少。MMP3沉默部分模拟了大黄提取物的抗铁死亡效应，而MMP3过表达削弱了其细胞保护活性。分子对接、分子动力学模拟和SPR分析支持代表性大黄成分与MMP3之间的直接相互作用。在体内，大黄提取物减轻了牙周炎症、胶原降解、铁沉积、破骨细胞形成和牙槽骨丧失。大黄提取物通过抑制炎症、铁死亡相关脂质过氧化和破骨细胞介导的骨吸收来减轻实验性牙周炎，部分通过调节MMP3相关的炎症-铁死亡轴实现。
Abstract
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. This study investigated whether rhubarb extract alleviates periodontal inflammatory injury and explored the role of matrix metalloproteinase 3 (MMP3) in periodontitis and ferroptosis. 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. 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. 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.
如何引用
AMA
Yifei Hou, Chongzheng Yan, Hongxu Zhao, Zihan Yang, Yijing Li, Xiamei Lu, et al. Rhubarb extract attenuates periodontitis by modulating an MMP3-associated inflammatory-ferroptotic axis: Integrated multi-omics analysis and experimental validation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158632.
APA
Yifei Hou, Chongzheng Yan, Hongxu Zhao, Zihan Yang, Yijing Li, Xiamei Lu, et al (2026). Rhubarb extract attenuates periodontitis by modulating an MMP3-associated inflammatory-ferroptotic axis: Integrated multi-omics analysis and experimental validation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158632
GB/T 7714
Yifei Hou, Chongzheng Yan, Hongxu Zhao, Zihan Yang, Yijing Li, Xiamei Lu, et al. Rhubarb extract attenuates periodontitis by modulating an MMP3-associated inflammatory-ferroptotic axis: Integrated multi-omics analysis and experimental validation.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158632.
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