Discovery of natural small-molecules to combat kidney fibrosis

Chronic kidney disease (CKD) has become one of the greatest threats to public health, characterized by renal fibrosis. However, no treatment targeting renal fibrosis is available so far. Several natural diterpene compounds exhibit extraordinary inhibitory effects on TGF-β1-induced renal fibroblast activation and renal fibrosis in UUO mouse model. RNA-sequencing reveals the signaling pathways affected by these compounds. The direct target of the compounds are explored via quantitative mass spectrometry. Besides, the efficacies of the compounds are compared with pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, which is under clinical trials for treating CKD patients. Moreover, these compounds exhibit more potent anti-fibrotic activities than conventional CKD medications such as valsartan and enalapril. Taken together, our study discovered that these diterpeniods alleviate kidney fibrosis by blocking the pro-fibrotic signaling pathway, which has great potential for the treatment of CKD.慢性肾脏病（Chronic kidney disease, CKD）已成为威胁公共健康的重大问题之一，其核心病理特征为肾纤维化。但目前尚无针对肾纤维化的获批治疗手段。多项天然二萜类化合物在单侧输尿管梗阻（Unilateral Ureteral Obstruction, UUO）小鼠模型中，对转化生长因子-β1（Transforming growth factor-β1, TGF-β1）诱导的肾成纤维细胞活化及肾纤维化表现出显著抑制作用。研究人员通过RNA测序（RNA-sequencing）揭示了此类化合物所影响的信号通路，并借助定量质谱技术探究了其直接作用靶点。此外，团队将此类化合物的疗效与吡非尼酮（Pirfenidone）进行对比——吡非尼酮是美国食品药品监督管理局（Food and Drug Administration, FDA）批准用于特发性肺纤维化的药物，目前正处于治疗慢性肾脏病患者的临床试验阶段。不仅如此，相较于缬沙坦（Valsartan）、依那普利（Enalapril）等常规慢性肾脏病治疗药物，此类化合物展现出更强的抗纤维化活性。综上，本研究证实此类二萜类化合物可通过阻断促纤维化信号通路缓解肾纤维化，在慢性肾脏病治疗领域具备巨大应用潜力。