Frontiers in pharmacology · 2026
Genkwanin mitigates renal fibrosis by reprogramming profibrotic signaling and restoring TFEB-mediated autophagy.
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Wang Shen, He Yu, Gan Xin, Kang Hao, Zhou Zhu, He ZongHai
Аннотация
BACKGROUND: Renal fibrosis is a common pathological outcome of chronic kidney disease and is characterized by persistent profibrotic signaling and impaired cellular homeostasis. Genkwanin (GAK), a natural flavonoid compound, has shown anti-inflammatory and antioxidant activities in several disease models. However, its role in renal fibrosis remains unclear.
MATERIALS AND METHODS: We investigated the antifibrotic effects of GAK in a TGF-β1-induced HK-2 cell model and a unilateral ureteral obstruction (UUO) mouse model. EMT- and fibrosis-related changes were assessed by RT-qPCR, Western blotting, immunofluorescence, and histological staining. The involvement of TGF-β1/SMAD2 and β-catenin signaling was examined using pharmacological modulators. Autophagic flux was evaluated by tandem mCherry-GFP-LC3 analysis, transmission electron microscopy, and autophagy-related protein expression. TFEB inhibition was used to further assess the role of lysosome-autophagy regulation.
RESULTS: GAK significantly attenuated TGF-β1-induced EMT and extracellular matrix accumulation in HK-2 cells and reduced renal fibrotic injury in UUO mice. Mechanistically, GAK decreased p-SMAD2 expression and limited β-catenin nuclear redistribution, indicating suppression of both TGF-β1/SMAD2 and β-catenin signaling. In addition, GAK improved autophagic flux and increased TFEB expression. Inhibition of TFEB partially weakened the protective effects of GAK on fibrosis-related and autophagy-related changes, suggesting that TFEB-mediated lysosome-autophagy function contributes to its antifibrotic action.
CONCLUSION: In conclusion, GAK alleviates renal fibrosis in vitro and in vivo, at least in part, by suppressing TGF-β1/SMAD2 and β-catenin signaling and by restoring TFEB-associated autophagic flux.
MATERIALS AND METHODS: We investigated the antifibrotic effects of GAK in a TGF-β1-induced HK-2 cell model and a unilateral ureteral obstruction (UUO) mouse model. EMT- and fibrosis-related changes were assessed by RT-qPCR, Western blotting, immunofluorescence, and histological staining. The involvement of TGF-β1/SMAD2 and β-catenin signaling was examined using pharmacological modulators. Autophagic flux was evaluated by tandem mCherry-GFP-LC3 analysis, transmission electron microscopy, and autophagy-related protein expression. TFEB inhibition was used to further assess the role of lysosome-autophagy regulation.
RESULTS: GAK significantly attenuated TGF-β1-induced EMT and extracellular matrix accumulation in HK-2 cells and reduced renal fibrotic injury in UUO mice. Mechanistically, GAK decreased p-SMAD2 expression and limited β-catenin nuclear redistribution, indicating suppression of both TGF-β1/SMAD2 and β-catenin signaling. In addition, GAK improved autophagic flux and increased TFEB expression. Inhibition of TFEB partially weakened the protective effects of GAK on fibrosis-related and autophagy-related changes, suggesting that TFEB-mediated lysosome-autophagy function contributes to its antifibrotic action.
CONCLUSION: In conclusion, GAK alleviates renal fibrosis in vitro and in vivo, at least in part, by suppressing TGF-β1/SMAD2 and β-catenin signaling and by restoring TFEB-associated autophagic flux.