Flavokawain A Attenuated Chronic Kidney Disease: Evidence From Network Pharmacology and Experimental Verification

Abstract

Chronic kidney disease (CKD) is a silent global epidemic affecting ~700 million people worldwide, contributing to rising mortality rates. Despite the variety of underlying causes, renal fibrosis is the key pathological feature of CKD. Flavokawain A (FKA), a natural chalcone, is thought to offer protective effects against CKD through its anti-inflammatory, antioxidant, and anti-fibrotic properties. This study aims to investigate the therapeutic potential of FKA against CKD, using network pharmacology (NP), molecular docking analysis, and In Vivo validation. GeneCards, SwissTargetPrediction, and SuperPred databases were utilized to identify therapeutic targets related to CKD and FKA. Protein–protein interactions (PPIs) were performed using the STRING database. Gene ontology and pathway enrichment analyses were performed with DAVID databases, followed by network construction in Cytoscape. For validation, molecular docking studies were performed using PyRx and tested at doses of 50 mg/kg and 100 mg/kg (p.o.) for 21 days using a unilateral ureteral obstruction (UUO) rat model. The study identified 109 therapeutic targets for FKA in relation to CKD, highlighting 11 hub targets and 78 potential pathways. Molecular docking showed strong binding efficacy with nuclear factor κB subunit 1 (NF-κB1) and matrix metallopeptidase 9 (MMP9). In vivo validation supported these findings, as FKA administration showed protective effects on kidney function and histology with the downregulation of extracellular matrix (ECM) markers, such as fibronectin (FN) and transforming growth factor β1 (TGF-β1), along with reduced expression of NF-κB1 and MMP9. These findings indicate that FKA could be a valuable therapeutic candidate for managing CKD by targeting NF-κB1 and MMP9.