2. Academic Validation
  3. A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling

A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling

  • Adv Sci (Weinh). 2024 Jan 19:e2307850. doi: 10.1002/advs.202307850.
Xinrong Hu 1,  Lu Gan 2,  Ziwen Tang 1,  Ruoni Lin 1,  Zhou Liang 1,  Feng Li 1,  Changjian Zhu 1,  Xu Han 1,  Ruilin Zheng 1,  Jiani Shen 1,  Jing Yu 1,  Ning Luo 1,  Wenxing Peng 1,  Jiaqing Tan 1,  Xiaoyan Li 1,  Jinjin Fan 1,  Qiong Wen 1,  Xin Wang 1,  Jianbo Li 1,  Xunhua Zheng 1,  Qinghua Liu 1,  Jianping Guo 3,  Guo-Ping Shi 4,  Haiping Mao 1,  Wei Chen 1,  Sheng Yin 2,  Yi Zhou 1
Affiliations

Affiliations

  • 1 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.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 4 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
PMID: 38240457 DOI: 10.1002/advs.202307850
Abstract

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.

Keywords

Cdc42; GSK-3β/β-catenin; kidney fibrosis; natural small molecules.

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