HCQ is a multi-targets antimalarial drug, which is widely used in rheumatology. However, the exact pharmacological mechanism is still unclear. As one of the DMARDs, HCQ could relief RA activity and improve the prognosis of it. Antimalarial agents have numerous biological effects that are responsible for their immunomodulatory actions [5–8]. According to our results of network pharmacology, SMO, SPHK1, SPHK2 and FAAH1 play vital roles of HCQ in the treatment of RA.
Synovitis is the main characteristic of RA. Excessive proliferation of fibroblast-like synoviocytes (FLSs) and synovial angiogenesis are the most important contributors to the progression of RA synovitis and joint destruction. Sonic hedgehog (SHH) signaling pathway plays a pivotal role in FLSs proliferation in a SMO-dependent manner. Upregulation of SMO promotes proliferation of FLSs [17–18]. Targeting SHH signaling pathway may help control joint damage in patients with RA . According to our analysis by network pharmacology, the binding of HCQ with SMO is involved in the pathological process of synovitis through the SHH pathway (Fig. 5).
SPHK (including SPHK1 and SPHK2) is a key lipid kinase in sphingolipid metabolic pathway, which phosphorylate phingosine into sphingosine-1-phosphate (S1P) [20–21]. The importance of SPHK and S1P in inflammation and angiogenesis has been demonstrated in many hyperproliferative/inflammatory diseases such as RA . The level of S1P exhibits significantly higher than those non-inflammatory osteoarthritis counterparts . Furthermore, S1P receptor was found to be expressed in RA synovium, which means that inflammatory cytokines would further promote the progress of synovitis . As mentioned above, excessive proliferation of FLSs was induced mainly through SHH pathway. In addition, inflammatory further accelerate the process through mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. For instance, interleukin 6, tumor necrosis factor-α, angiopoietin 1, neuropilin 1 and vascular endothelial growth factor regulate the lesion of rheumatoid joint and the proliferation of FLSs through the MAPK/ERK pathway . SphK blockade suppresses cytokines and MMP-9 release in RA peripheral blood mononuclear cells . Targeting SPHK may help control joint damage in aspect of inflammation. According to our analysis by network pharmacology, the binding of HCQ with SPHK1 and SPHK2 plays important role in inhibiting the inflammatory process of synovitis (Fig. 5).
In recent years, the role of the endocannabinoid (EC) system in the pathogenesis of RA attracted more attention of researchers. EC system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in RA . The action of EC system in immune system regulation, via primary cannabinoid receptor (CB) activation, followed by inhibition of production of pro-inflammatory cytokines, auto-antibodies and matrix metalloproteinase (MMPs), FLSs proliferation and T-cell mediated immune response . Since FAAH is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is promising . Thus, due to the result of network pharmacology, the binding of HCQ with FAAH acts as one of the multi-targets mechanism in the treatment of RA (Fig. 5).