# The Immunogenetics of Psoriasis and Implications for Drug Repositioning
## 3 Implications for Drug Repositioning
_STAT3_-related skin diseases are characterized by epidermal hyperplasia and abnormal differentiation. _STAT3_ performs its biological function by regulating several genes associated with apoptosis and proliferation and has been the focus of recent clinical research [45]. It is present in the cytoplasm of untreated cells and can be affected by the cytokines _IL-6_ and _IL-10_, epidermal growth factor (_EGF_), hepatocyte growth factor (_HGF_), human epidermal growth factor receptor 2 (_HER2/Neu_), vascular endothelial growth factor (_VEGF_), and other ligands along with human erythropoietin (_EPO_) and human granulocyte-macrophage colony stimulating factor (_GM-CSF_), among other factors. \begin{table}
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Psoriasis patients mainly express _VEGF_ in the cytoplasms of keratinocytes from the basal layer to the granular layer. Contrastingly, _VEGF_ has little or no expression in normal epidermis. In psoriasis patients, the _STAT3_ protein is located in the cytoplasm and nuclei of the whole or middle layer of the epidermis, whereas _STAT3_ is only present in the cytoplasm of the epidermal basal layer in normal epidermis. Therefore, _VEGF_ and _STAT3_ protein expression levels are higher in the skin lesions of psoriasis patients than in normal skin. Studies have shown that both proteins exhibit synergistic effects in psoriasis pathogenesis [46]. _EGFR_ is a member of the epidermal growth factor family and is a transmembrane glycoprotein present on the surfaces of keratinocytes. It exhibits tyrosine kinase activity and plays important roles in the activation phases of proliferative signaling pathways. Its main ligands are epidermal growth factor (_EGF_) and _TGF-\(\alpha\)_, among others; _TGF-\(\alpha\)_ can be formed by keratinocytes and then act in an autocrine manner, and _EGFR_ can combine into dimers. Stimulation of the intrinsic tyrosine kinase function activates _EGFR_, which triggers downstream signal transduction pathways, such as RAS/ mitogen-activated protein kinases (MAPK), _P13/AKT_, and Janus kinase (JAK)/STAT, and it is found in many tumors. Drugs for _STAT3_ are under investigation and have achieved satisfying therapeutic efficacy. One example is Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH), a simple and interesting synthetic derivative of a natural compound separated from sponges, which can reduce the proliferation of keratinocytes by inhibiting the anti-inflammatory activity of the NF-kB signaling pathway and impair _STAT3_ phosphorylation, preventing it from translocating to the nucleus and resulting in a decrease in keratinocyte proliferation [45]. As mentioned earlier, recent studies have also found interleukin 1B (_IL-1B_), tumor necrosis factor (_TNF_) [47], vitamin D receptor (_VDR_) [48], nitric oxide synthase 3 (_NOS3_) [49], and other genes to be overexpressed in psoriasis patients (GOF). Therefore, we used inhibitors for these targets and in turn designed drug repositioning strategies for psoriasis. By performing psoriasis-related patent and literature searches, we found 12 of these drugs to be previously reported, further demonstrating our target-based drug repositioning method to have a high degree of accuracy and also indicating that the drugs we predicted by this method to be promising for psoriasis treatment (results summarized in Table 3).