Exploring the Therapeutic Potential and Underlying Mechanism of Bergapten in Renal Fibrosis: Network Pharmacology, Molecular Docking, and Experimental Validation

ABSTRACT Chronic kidney disease (CKD) is characterized by progressive interstitial fibrosis, contributing to high global mortality due to limited treatment options. Contemporary findings highlight the potential of natural compounds for CKD treatment. Bergapten (BGT), a bioactive furocoumarin, is recognized for its antioxidant and anti‐inflammatory properties but remains unexplored as an antifibrotic agent. The potential targets of BGT were identified using network pharmacology and in silico approaches. The antifibrotic effects of BGT were evaluated in transforming growth factor (TGF)‐β1–induced normal rat kidney fibroblast (NRK‐49F) cells. For in vivo validation, CKD was induced in mice using unilateral ureteral obstruction (UUO). Immunocytochemistry, histopathological analysis, and immunoblotting were conducted to assess the effects of BGT on fibroblast activation, renal microstructural changes, and expression of profibrotic markers. Network pharmacology analysis revealed 119 BGT‐target genes involved in renal fibrosis, including those in the TGF‐β1 signaling pathway. Molecular docking confirmed the interaction of BGT with TGF‐β receptor 1 (TGFR1). In vitro studies demonstrated that BGT (30 μM) inhibited TGF‐β1‐induced fibrotic response in NRK‐49F cells by inhibiting TGF‐β1/Smad signaling. In vivo, oral administration of BGT (20 mg/kg) improved kidney function and alleviated histological damage, and pathological collagen deposition while mitigating renal inflammation. BGT suppressed the TGF‐β1/Smad signaling pathway, reduced the expression of extracellular matrix (ECM) proteins, and mitigated oxidative stress by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme‐oxygenase‐I (HO‐I) signaling pathway. This study demonstrated the therapeutic potential of BGT in alleviating renal fibrosis in experimental models of CKD. The observed effects were attributed to the inhibition of TGF‐β1/Smad signaling and activation of the Nrf2 pathway.