Finerenone alleviates the high glucose-induced fibrosis in HK-2 cells by inhibiting EMT via the TGF-β1/Smads signaling.

Finerenone is a novel non-steroidal mineralocorticoid receptor antagonist and exhibits anti-fibrotic effects against diabetic nephropathy (DN), but its underlying mechanism of action remains unclear. This study aimed to elucidate the effects of Finerenone on high glucose (HG)-induced fibrosis in HK-2 cells and explore the underlying mechanisms. Finerenone was used to treat HG-stimulated HK-2 cells. ELISA and immunofluorescence assays were used to evaluate extracellular matrix (ECM) accumulation and epithelial-to-mesenchymal transition (EMT). Western blotting and molecular docking were performed to investigate the interaction of Finerenone with TGF-β1/Smad signaling. ALK5 knockdown experiments were conducted to confirm Finerenone's target specificity. Finerenone significantly reduced HG-induced fibronectin, collagen III, collagen IV and α-SMA expression. Moreover, Finerenone restored E-cadherin while suppressed N-cadherin and vimentin levels. Notably, it did not alter TGF-β1 production, but inhibited Smad2/3 phosphorylation. Molecular docking showed its competitively binding site to TGF-βR1, knockdown of which abolished Finerenone's anti-fibrotic effects. Finerenone mitigates HG-induced fibrosis in HK-2 cells by targeting TGF-βR1 and inhibiting downstream Smad signaling to modulate ECM accumulation and EMT. These findings provided mechanistic insights into Finerenone's potential as a therapeutic agent for DN.