The chalcone derivative DN-053 attenuates renal fibrosis and inhibits p38 MAPK and STAT3 signaling in renal fibroblasts.

Renal fibrosis is the final common pathway of chronic kidney disease and is largely driven by transforming growth factor-β1 (TGF-β1) signaling. TGF-β1 exerts its cellular effects via two main signaling pathways: the canonical Smad-dependent pathway and non-canonical Smad-independent pathways, including MAPK and STAT3 signaling. This study investigated the anti-fibrotic effects of a novel chalcone derivative, DN-053, in vitro and in vivo. In NRK-49F renal fibroblasts, DN-053 dose-dependently inhibited TGF-β1-induced α-smooth muscle actin (α-SMA) expression with an IC50 of 1.13 µM and reduced fibroblast proliferation. DN-053 also attenuated α-SMA expression in established myofibroblasts, suggesting reversibility of activation. Mechanistically, in vitro, DN-053 did not alter Smad3 phosphorylation but significantly suppressed TGF-β1-induced activation of p38 MAPK and STAT3. In a unilateral ureteral obstruction (UUO) mouse model, DN-053 (10 mg/kg/day, i.p.) significantly reduced interstitial collagen deposition and decreased renal expression of collagen I, α-SMA, and TGF-β protein. Collectively, these findings demonstrate that DN-053 exerts potent anti-fibrotic effects in vitro and attenuates renal fibrosis in vivo, supporting further preclinical evaluation of DN-053 as a promising anti-fibrotic lead compound.