虫草素在延缓CKD进程中的作用机制研究进展

Cordycepin in Delaying the Progression of CKD: Mechanisms of Action Research Progress

摘要: 慢性肾脏病(CKD)发病率呈上升趋势，其进展涉及炎症、氧化应激和纤维化等多重病理机制。虫草素(3’-脱氧腺苷)作为蛹虫草的主要活性成分，在延缓CKD进程中展现出多靶点干预潜力。在抗炎方面，虫草素可剂量依赖性降低TLR4、NF-κB p65及下游COX-2的表达，抑制TGF-β1诱导的Smad1/2/3磷酸化，减少胶原沉积和上皮–间质转化，并使CKD患者血清IL-1β、TNF-α水平降低14.0%~26.9%。在抗氧化方面，虫草素可直接清除活性氧，提高超氧化物歧化酶、谷胱甘肽过氧化物酶活性，降低丙二醛含量；并通过激活Nrf2-ARE通路增强内源性抗氧化防御，抑制NF-κB及TGF-β1/Smad通路以阻断氧化应激与炎症的恶性循环。在抗纤维化方面，虫草素可直接结合Drp1蛋白(KD = 2.75 μM)，抑制线粒体过度分裂，减少线粒体源性ROS生成，进而下调IL-6表达及JAK/STAT3通路活化；同时诱导肝细胞生长因子表达，抑制α-SMA和纤连蛋白沉积。此外，虫草素还能通过调节腺苷受体亚型分布，特异性激活A₁AR/A₂AAR并拮抗A₂BAR/A₃AR，改善CKD病理微环境。综上，虫草素通过多维度机制减轻肾脏炎症、氧化损伤与纤维化，为CKD的干预提供了潜在治疗策略。

Abstract: The incidence of Chronic Kidney Disease (CKD) is increasing, and its progression involves multiple pathological mechanisms such as inflammation, oxidative stress, and fibrosis. Cordycepin (3’-deoxyadenosine), a major bioactive component of Cordyceps militaris, demonstrates multi-target intervention potential in delaying CKD progression. Regarding its anti-inflammatory effects, cordycepin can dose-dependently reduce the expression of TLR4, NF-κB p65, and downstream COX-2, inhibit TGF-β1-induced phosphorylation of Smad1/2/3, reduce collagen deposition and epithelial-mesenchymal transition, and decrease serum levels of IL-1β and TNF-α by 14.0% to 26.9% in CKD patients. In terms of antioxidant activity, cordycepin can directly scavenge reactive oxygen species, increase the activity of superoxide dismutase and glutathione peroxidase, lower malondialdehyde content, enhance endogenous antioxidant defenses by activating the Nrf2-ARE pathway, and inhibit the NF-κB and TGF-β1/Smad pathways to break the vicious cycle between oxidative stress and inflammation. For its anti-fibrotic action, cordycepin can directly bind to Drp1 protein (KD = 2.75 μM), inhibit excessive mitochondrial fission, reduce mitochondrial-derived ROS production, subsequently downregulate IL-6 expression and JAK/STAT3 pathway activation, and induce hepatocyte growth factor expression to inhibit α-SMA and fibronectin deposition. Furthermore, cordycepin can improve the pathological microenvironment of CKD by modulating adenosine receptor subtype distribution, specifically activating A₁AR/A₂AAR and antagonizing A₂BAR/A₃AR. In conclusion, cordycepin alleviates renal inflammation, oxidative damage, and fibrosis through multi-dimensional mechanisms, providing a potential therapeutic strategy for CKD intervention.