MicroRNA-718 inhibits mitochondrial fusion and ameliorates IMQ-induced psoriasis inflammation mediated by PHB and STAT1

Multiple inflammatory pathways contribute to the development of psoriasis, leading to the hyperproliferation and dedifferentiation of keratinocytes at the affected site. The precise etiology of psoriasis pathogenesis remains unclear. Given that a single miRNA can regulate a cellular process involving multiple genes, there has been a rise in miRNA-based therapy studies over the past few decades. The current study aimed to investigate the therapeutic potential of miR-718 overexpression in treating psoriasis and to elucidate its underlying mechanisms using an imiquimod (IMQ)-induced mouse model and human keratinocytes (HaCaT). Additionally, the drug tofacitinib was incorporated in the in-vivo study to provide further insights. We observed that miR-718 overexpression leads to the inhibition of JAK/STAT signaling, as evidenced by the reduced expression of STAT1, JAK1, JAK2, and JAK3, directly inhibiting STAT1, both in-vitro and in-vivo . Moreover, the expression of STAT2 and STAT3 was also found to be downregulated in in-vitro studies. In-vivo studies further show that miR-718 decreases the NF-kB, critical mediators of inflammation, upon ectopic expression in psoriatic mice. Immunohistochemistry (IHC) results indicate reduced acanthosis and parakeratosis in IMQ-induced psoriatic mice, potentially resulting from halted JAK/STAT signaling. In the miR-718 transfected mice skin, there was decreased expression of VEGF and matrix metalloproteases (MMP7 and MMP9), as shown by IHC and western blotting, respectively. The study also demonstrated that miR-718 represses mitochondrial fusion by inhibiting MFN1, MFN2, PHB, and OPA1 in HaCaT cells, while increasing DRP1 expression. Understanding the mechanism by which miR-718 ameliorates psoriasis not only provides new insight but also raises hopes for translating miR-718 as potential therapeutic agent for psoriasis.