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Genkwanin mitigates renal fibrosis by reprogramming profibrotic signaling and restoring TFEB-mediated autophagy
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DOI：10.3389/fphar.2026.1861855.png)
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Abstract
En 中文
BackgroundRenal 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 methodsWe 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.ResultsGAK 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.ConclusionIn 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.
Keywords:
autophagy
LC3
renal fibrosis
TFEB
genkwanin
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