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| 乌头汤调控 HIF-1α/糖酵解轴改善膝骨关节炎机制研究 |
| Mechanism of Wutou Decoction in the regulation of the HIF-1α/Glycolysis Axis to ameliorate knee osteoarthritis |
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| DOI：10.3969/j.issn.1006-7108.2026.09.005 |
| 中文关键词: 乌头汤 骨关节炎 HIF-1α 糖酵解重编程 |
| 英文关键词:Wutou Decoction osteoarthritis HIF-1α glycolytic reprogramming |
| 基金项目:广州市科技计划项目（2023B03J0056）；广东省基础与应用基础研究项目（2024A1515012062） |
| 作者 | 单位 | | 肖嘉聪1,2,3 王厚元1,2,3 王婷1,2,3 林郁桐1,2,3 吴昱宸1,2,3 王海彬1,2,3,4* 刘毅1,5* | 1.广州中医药大学,广东 广州 510405
2.广州中医药大学第一临床医学院,广东 广州 510405
3.广州中医药大学岭南医学研究中心,广东 广州 510405
4.广州中医药大学第一附属医院骨伤中心,广东 广州 510405
5. 广州中医药大学第一附属医院足踝骨科,广东 广州 510405 |
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| 中文摘要: |
| 目的 探讨乌头汤对膝骨关节炎的干预作用及其潜在分子机制。方法 通过网络药理学预测乌头汤的作用靶点与信号通路。采用前交叉韧带切断术（anterior cruciate ligament transection，ACLT）建立膝骨关节炎（knee osteoarthritis，KOA）大鼠模型，予以乌头汤干预。通过 Micro-CT与组织学染色评估软骨及软骨下骨结构改变；检测膝关节软骨中乳酸、丙酮酸水平及血清炎症因子肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-6（interleukin-6，IL-6）水平；qPCR、Western blot与免疫组化检测关节软骨组织中低氧诱导因子-1α（hypoxia inducible factor-1α，HIF-1α）及糖酵解关键酶己糖激酶2（hexokinase 2，HK2）、丙酮酸激酶M2（pyruvate kinase isozyme type M2，PKM2）、乳酸脱氢酶A（lactate dehydrogenase A，LDHA）的表达。结果 网络药理学结果表明，乌头汤可能通过HIF1-α信号通路治疗KOA。体内实验结果表明，乌头汤可明显改善 KOA大鼠软骨退变；Micro-CT显示其减轻软骨下骨破坏；乌头汤可降低膝关节软骨中乳酸、丙酮酸活性水平及血清TNF-α、IL-6含量。机制研究发现，乌头汤能够下调 HIF-1α及其下游 HK2、PKM2、LDHA的表达，抑制乳酸过度生成和酸性微环境形成，从而改善软骨细胞能量代谢障碍。结论 乌头汤通过调控HIF-1α信号通路抑制糖酵解重编程，从而缓解KOA大鼠膝关节软骨退变，显示出其在骨关节炎防治中的重要应用潜力，并为其临床应用提供了理论依据。 |
| 英文摘要: |
| Objective To investigate the therapeutic effects of Wutou Decoction (WTD) on knee osteoarthritis (KOA) and its potential molecular mechanisms. Methods Network pharmacology was employed to predict the potential targets and signaling pathways of WTD. A KOA rat model was established using anterior cruciate ligament transection (ACLT) surgery. WTD intervention was followed. Micro-CT and histological staining were used to evaluate structural changes in the cartilage and subchondral bone. The levels of lactate and pyruvate in the articular cartilage, as well as serum inflammatory cytokines TNF-α and IL-6, were measured using commercial assay kits. The expressions of HIF-1α and key glycolytic enzymes (HK2, PKM2, and LDHA) in the articular cartilage were assessed using qPCR, Western blotting, and immunohistochemistry, respectively. Results Network pharmacology analysis indicated that WTD exerted its therapeutic effect on KOA through the HIF-1α signaling pathway. In vivo experiments demonstrated that WTD significantly ameliorated cartilage degeneration in KOA rats. Micro-CT results further revealed that WTD alleviated subchondral bone destruction. Moreover, WTD reduced the levels of lactate and pyruvate in the cartilage tissue, as well as serum TNF-α and IL-6. Mechanistically, WTD down-regulated the expressions of HIF-1α and its downstream glycolytic enzymes HK2, PKM2, and LDHA, thereby suppressing excessive lactate production and the formation of the acidic microenvironment, ultimately relieving energy metabolism disorders in chondrocytes. Conclusion WTD alleviates KOA-related cartilage degeneration by modulating the HIF-1α signaling pathway and by inhibiting glycolytic reprogramming. These findings indicate the therapeutic potential of WTD in osteoarthritis and provide a theoretical basis for its clinical application. |
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