Computational repurposing and preclinical validation of colquhounia root tablets for membranous nephropathy

Dear Editor, Current therapeutics of membranous nephropathy (MN) hold dilemmas of limited clinical response rates, high recurrence rate, and unavoidable adverse effects.1 Colquhounia Root Tablet (CRT) is a Chinese patent medicine prepared from the peeled root of Tripterygium hypoglaucum (Lévl.) Hutch (SFDA approval number: Z20027411). Emerging clinical evidence has indicated a potential therapeutic effect of CRT on MN.2,3 However, the mechanisms of CRT against MN remain unclear. In this study, 585 putative targets of CRT were predicted hit by chemical compounds identified by UPLC-Q-TOFMS (Figure S1 and Table S1) and collected from literatures (Table S2).4,5 Then, 692 MN-related genes were collected by searching clinical symptoms and the related genes (Table S3). After constructing the ‘disease-related genesdrug putative targets’ interaction network using the links among MN-related genes and CRT putative targets, a total of 49 key network targets were selected by calculating nodes’ topological features (Table S4). Functionally, the key putative targets of CRT against MN were significantly enriched in 11 signalling pathways, including JAK-STAT signalling, TNF signalling, PI3K-Akt signalling and etc. (all p < .001, Figure 1A). In the most enriched ‘immunization’ module, tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and their downstream partners (JAK2, STAT3, MMP9) formed a signal axis that may play an essential role in the pathogenesis of MN. Thus, we hypothesized that CRT might alleviate the severity of MN through regulating TNF-α-IL-6-JAK2/STAT3-MMP9 signalling axis (Figure 1B,C). To evaluate the effects of CRT on cationic bovine serum albumin (C-BSA) induced MN mice, kidney index, levels of microalbumin from 24 h urine, creatinine, total cholesterol and serum albumin were detected after the routine induction of MN mice and drug treatment (Figure 2A). The microalbumin levels from 24 h urine were significantly increased in MN mice from the 4th week till the end of the experiment (p < .001, Figure 2B). MN mice