Kunxian capsule alleviates renal damage by inhibiting the JAK1/STAT1 pathway in lupus nephritis.

Abstract

Kunxian capsule (KXC) is a new traditional Chinese medicine drug included in "The key science and technology achievements" in the Ninth Five Year Plan of China. KXC has been clinically used for more than 10 years in the treatment of lupus nephritis (LN). However, the underlying role and molecular mechanism of KXC in LN remain unclear. This study aimed to explore the efficacy and potential mechanisms of KXC through pharmacological network, in vitro and in vivo studies. Pharmacological network analysis of KXC treatment in LN was performed using data acquired from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP, https://old.tcmsp-e.com/tcmsp.php) and NCBI Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/database). HK-2cells were chosen as an in vitro model of the tubular immune response by simulation with interferon γ (IFN-γ). MRL/lpr mice were used to explore the mechanism of KXC in vivo. Finally, the specific active molecules of KXC were further analyzed by molecular docking. The pharmacological network analysis showed that STAT1 is a key factor in the effects of KXC. In vitro and in vivo experiments confirmed the therapeutic effect of KXC on LN renal function and tubular inflammation. The protective effect of KXC is mediated by STAT1 blockade, which further reduces T-cell infiltration and improves the renal microenvironment in LN. Two main components of KXC, Tripterygium hypoglaucum (H.Lév.) Hutch (Shanhaitang) and Epimedium brevicornu Maxim (Yinyanghuo) could block JAK1-STAT1 activation. Furthermore, we found 8 molecules that could bind to the ATP pocket of JAK1 with high affinities by performing docking analysis. KXC inhibits renal damage and T-cell infiltration in LN by blocking the JAK1-STAT1 pathway.