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

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. The natural compound DA, screened out from 16 diterpenoids extracted from Wikstroemia chamaedaphne, alleviates kidney fibrosis by blocking fibroblast activation in the pro‐fibrotic environment. DA binds to Cdc42 and inhibits p‐PKCζ/p‐GSK‐3β axis, thereby promoting the ubiquitinated proteolysis of β‐catenin and suppressing its downstream pro‐fibrotic signals.