HN could eventually lead to renal failure (RF), seriously threatening the life and health of patients [7–8]. Currently, the drugs of clinical treatment in HN are mainly divided into inhibition of UA synthesis, increase of UA excretion, promote UA decomposition. As mentioned above, these drugs are limited when the glomerular filtration rate decreases and probably cause a range of adverse reactions. With the development of TCM, a new therapeutic direction has been provided. Studies have shown that SMP can also enhance renal UA excretion ability, reduce UA level and improve renal insufficiency of hyperuricemia mice by regulating renal organic anion transporter in hyperuricemia mice . Due to fewer adverse reactions and lower cost, SMP has attracted increasing interest in recent years. This research is to unravel the mechanism and molecular docking of SMP in the treatment of HN.
According to Fig. 4 and Table 1, it could be concluded that quercetin, baicalein, kaempferol and others were the main active components of SMP. Quercetin, a typical flavonoid, was the main component of Cortex Phellodendri and Radix Vladimiriae. Studies have suggested that quercetin can decrease UA and protect kidney by regulating the expression levels of renal tissue transporter and urinary regulatory protein . Quercetin has also been reported to relieve HN by regulating NLRP3 inflammasome and TLRs signaling pathway . Baicalein and kaempferol were the active compound of Radix Vladimiriae. Baicalein inhibits inflammation by down-regulating NF-κB, mitogen-activated protein kinase (MAPK), PI3K-Akt and other pathways . Kaempferol belongs to the flavonol group. It has been reported that kaempferol significantly increase antioxidant resistance and suppress xanthine oxidase (XOD) in hyperuricemia rats . In addition, quercetin , stigmasterol , baicalein  can reduce UA level by inhibiting the activity of XOD in hyperuricemia mice. SMP  can down-regulate URAT1 and up-regulate OAT1 renal UA transporter, inhibit XOD activity, and enhance antioxidant enzyme activity, so as to reduce UA level and protect kidney. It could be concluded that SMP and its various active ingredients can effectively reduce UA level and improve body injury by inhibiting XOD activity, regulating UA transporter, and anti-inflammation and anti-oxidation through multiple channels and multiple targets.
Related core target proteins of SMP active ingredients were obtained in the PPI network, such as VEGFA, PTGS2, IL-1β, CCL2, TP53, FN1, HIF1α, FOS, JUN, MMP9, CASP3, EGF, MMP2 and CXCL8. VEGFA plays crucial role in angiogenesis and maintenance of vascular stability. PTGS2 catalyzes the conversion of arachidonic acid to prostaglandins, which plays a major role in the biological environment, including homeostasis, gastric mucosal integrity, renal function, and inflammatory response . IL-1β is a pro-inflammatory gene and its expression increases gradually with the occurrence of inflammation. CCL2 can not only induce the aggregation of inflammatory cells such as neutrophils, monocytes and lymphocytes to the lesion site, but also induce the synthesis of other cytokines such as IL-2, IL-6 or cell adhesion molecules . TP53 is a well-known tumor suppressor gene. It can also indirectly regulate cell cycle regulation and DNA damage repair . Inhibition of p53 significantly promotes IL-1β induced chondrocyte senescence . The potential role of TP53 in inflammatory regulation is related to inhibit the proinflammatory cytokine IL-6 . It has been shown that overexpression of FN1 can result in activation of TGF-Akt/PI3K/Akt pathway promoting the survival of cells . HIF1α is considered as the master transcriptional regulator of cellular and developmental response to hypoxia, specifically in vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. C-Jun N-terminal kinase (JNK) is an important member of the MAPK family. Former studies pointed out that the JNK signaling pathway could possess a significant role in almost all physiological and pathological processes such as differentiation, proliferation and apoptosis of all cellular types . Studies have shown that in adenine nephropathy rats, the activation of JNK signaling pathway has an important role in in renal tubular epithelial cell apoptosis and renal injury . C-FOS is a highly conserved gene widely expressed at low levels in most cells, and is an important member of the immediate early gene family. C-FOS gene is highly expressed in renal tissue, and affects the occurrence and development of nephropathy by participating in the regulation of cell proliferation, differentiation, apoptosis, production of inflammatory factors and tissue fibrosis. Experimental studies  demonstrated that c-FOS expression was increased in renal tissues of rats with chronic glomerulonephritis, and the mechanism of c-FOS expression mediated by syK/Ras/C-FOS signaling pathway might be completed. The SYK/Ras/C-FOS pathway is activated by extracellular signaling molecules. Activate the downstream factor and eventually enhance c-fos expression. Activated FOS protein binds to c-Jun family proteins to form transcription factor AP-1, which increases the expression of tumor necrosis factor (TNF)-α, IL-8, IL-6 and other inflammatory factors, and participates in the inflammatory response in the course of chronic glomerulonephritis. MMP2 is a member of the MMP family. MMP2 is involved in the decomposition of glomerular ECM in the pathological process of various glomerular diseases [26, 27]. Epidermal growth factor receptor (EGFR) is widely expressed in the kidney of mammals with different cell types and regulates cell proliferation, differentiation and apoptosis by activating MAP kinase, JAK/STAT, SRC kinase and PI3K intracellular pathways [28–30]. CXCL8 is known chemokines for neutrophils . CXCL8 reduces pathological kidney damage and inflammatory cell infiltration in the kidney by inhibiting the inflammatory response induced by neutrophils . Caspase (CASP) 3 is a typical apoptotic effect CASP, which plays an extremely critical role in body development, apoptosis and inflammation . Overall, it is speculated that SMP acts as treating HN through anti-inflammation, apoptosis, cell cycle regulation and anti-oxidative stress, etc.
According to the results of enrichment analysis, many pathways containing NF-κB, IL-17, TNF, p53 and HIF-1 were found relating to the mechanism of SMP treating HN. IL-17 is a characteristic cytokine secreted by TH17 cells and participates in the inflammatory response in vivo. Studies have found that  regulatory T cells and TH17 cells play a vital role in the disease development of acute gout arthritis rats. However, IL-17 neutralizing antibody can reduce renal inflammatory infiltration in HN  and improve the symptoms of HN. It has been shown that increased UA level can induce apoptosis of renal tubular cells by disrupting the balance between anti-apoptotic and pro-apoptotic proteins . In addition, renal tubular epithelial cell apoptosis has also been observed in renal biopsies of patients with familial gout nephropathy . TNF signaling pathway is strongly correlated with the secretion of inflammatory factors in the body, and induced the activation of NF-κB, P38 α and their downstream effector kinase MK2 by binding to TNFR1 receptor, thereby promoting the transcription of target genes, mRNA stability and translation . It concluded that the bioactive components of SMP act on multiple targets to treat HN through multiple pathways.
There are still many deficiencies, such as the most active ingredient-target proteins were not confirmed by clinical experiment, the limitations of various platform databases and related software algorithms.