Forsythiaside A suppresses renal fibrosis and partial epithelial-mesenchymal transition by targeting THBS1 through the PI3K/AKT signaling pathway

Renal fibrosis is a key feature of chronic kidney disease (CKD) progression, whereas no proven effective anti-fibrotic treatments. Forsythiaside A (FTA), derived from Forsythia suspense, has been found to possess nephroprotective properties. However, there is limited research on its anti-fibrotic effects, and its mechanism of action remains unknown. This study aimed to investigate the suppressive effects of FTA on renal fibrosis and explore the underlying mechanisms. In vitro, we established a HK2 cell model induced by transforming growth factor β1 (TGF-β1), and in vivo, we used a mice model induced by unilateral ureteral obstruction (UUO). CCK-8 assay, qRT-PCR, Western blotting, immunofluorescence, flow cytometry, histological staining, immunohistochemistry, TUNEL assay, RNA transcriptome Sequencing, and molecular docking were performed. The results showed that FTA (40 μM or 80 μM) treatment improved cell viability and suppressed TGF-β1-induced fibrotic changes and partial epithelial-mesenchymal transition (EMT). Furthermore, FTA treatment reversed the activation of the PI3K/Akt signaling pathway, and THBS1 was identified as the target gene. We found that THBS1 knockdown suppressed the activation of the PI3K/Akt signaling pathway and reduced the fibrosis and partial EMT-related protein level. Conversely, THBS1 overexpression activated the PI3K/Akt signaling pathway and exacerbated renal fibrosis and partial EMT. In vivo, mice were administered FTA (30 or 60 mg/kg) for 2 weeks, and the results demonstrated that FTA administration significantly mitigated tubular injury, tubulointerstitial fibrosis, partial EMT, and Apoptosis. In conclusion, FTA inhibited renal fibrosis and partial EMT by targeting THBS1 and inhibiting activation of the PI3K/Akt pathway.

Forsythiaside A; PI3K/AKT signaling pathway; Renal fibrosis; THBS1; partial EMT.