Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, NHC Key Laboratory of Clinical Nephrology, Guangdong Provincial Key Laboratory of Nephrology, Sun Yat-Sen University, Guangzhou, 510080, China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Adv Sci (Weinh). 2024 Apr;11(13):e2307850. doi: 10.1002/advs.202307850. Epub 2024 Jan 19.
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3β (p-GSK-3β), thereby promoting β-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic β-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
肾纤维化是慢性肾脏病（CKD）的常见结局，最终导致肾功能衰竭。然而，针对这一病理过程，尚未有有效的治疗方法。在药用植物腊梅科腊梅属植物腊梅的生物活性导向化学研究中，发现了一种董氏二萜类化合物，即腊梅定 A（DA），是一种很有前途的抗肾纤维化先导化合物。DA 在培养的肾成纤维细胞和单侧输尿管梗阻小鼠中均显示出显著的抗肾纤维化作用，其活性强于临床试验药物吡非尼酮。利用热蛋白组学分析策略，鉴定出细胞分裂周期蛋白 42（Cdc42）是 DA 的直接靶点。DA 通过靶向降低 Cdc42 的活性并下调其下游磷酸蛋白激酶 Cζ（p-PKCζ）/磷酸糖原合成酶激酶-3β（p-GSK-3β），从而促进β-连环蛋白 Ser33/37/Thr41 磷酸化和泛素依赖性蛋白降解，阻断经典的促纤维化β-连环蛋白信号通路。这些发现表明 Cdc42 是治疗肾纤维化的一个很有前途的靶点，并突出了 DA 作为一种有效的 Cdc42 抑制剂，可用于治疗 CKD。
