Fufang Shenhua tablet (SHT), a traditional Chinese medicine compound, has been utilized in the clinical management of chronic kidney disease (CKD) for a long time. Nevertheless, the fundamental active constituents and potential mechanism of action remain unclear. Thus, the objective of this study was to investigate the renoprotective effect of SHT on residual renal tissue in CKD model rats and to explore its primary efficacious components and their underlying mechanism.After a 12-week period of SHT treatment through gavage in a 5/6 nephrectomized animal model of CKD, we evaluated the body weight, renal function, and renal pathological changes. Furthermore, the expression levels of fibronectin (FN), collagen I (COL-1), α-smooth muscle actin (α-SMA), and vimentin in renal tissues were assessed. In addition, network pharmacology analysis and molecular docking were utilized to predict the primary active components, potential therapeutic targets, and intervention pathways through which SHT could potentially exert its anti-kidney fibrosis effects. Subsequently, these predictions were validated in renal tissues of rats with CKD and in transforming growth factor β1 (TGF-β1)-induced HK-2 cells.SHT significantly improved renal function and reduced renal pathological damage and fibrosis in CKD model rats. Network pharmacological analysis identified 62 active components in SHT, with quercetin ranked first, and 105 protein targets shared by SHT and CKD. Based on the protein‒protein interaction network (PPI) and the SHT-CKD-pathway network, AKT1, MYC, IL2, and VEGFA were identified as key targets. Furthermore, GO and KEGG pathway enrichment analyses indicated that the renoprotective effect of SHT on CKD was closely associated with the PI3K/AKT signaling pathway. Molecular docking results demonstrated that the main active components of SHT had a strong binding affinity to the hub genes. During experimental validation, SHT hindered the activity of the PI3K/AKT signaling pathway in the renal tissue of CKD model rats. Furthermore, activation of the PI3K/AKT signaling pathway was correlated with a modified fibrotic phenotype in rats with 5/6 nephrectomy-induced CKD and TGF-β1-induced HK-2 cells. Conversely, SHT and quercetin curtailed the activation of the PI3K/AKT signaling pathway and inhibited the formation of renal fibrosis, thus indicating that the PI3K/AKT signaling pathway is the basis of the antifibrotic effects of SHT. Ultimately, administration of the PI3K/AKT agonist 740Y-P counteracted the fibrotic phenotype of TGF-β1-induced HK-2 cells induced by SHT.In this investigation, we employed a fusion of systems pharmacology and in vivo and in vitro experiments to elucidate the mechanism of SHT's antifibrotic properties via obstruction of the PI3K/AKT signaling pathway. Additionally, we surmised that AKT may be the principal target of SHT for the management of CKD and that quercetin may be its efficacious component. We have thus identified SHT as a promising drug for the amelioration of renal fibrosis and the progression of CKD.Copyright © 2023 Elsevier GmbH. All rights reserved.