Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice

Psoriasis is one kind of autoimmune skin disease without efficiency cure. Shikonin (SHK) is a potential drug for psoriasis treatment. Recent study suggested that ferroptosis involved in the pathological process of psoriasis. This study proved the beneficial effect of SHK with an imiquimod (IMQ) induced psoriatic model mice, and studied the ferroptosis regulative mechanism of SHK with a HaCaT cells assay in vitro. In the study, it also found that SHK treatment significantly improved imiquimod (IMQ)-induced psoriasis symptoms in mice, attenuated the production of inflammatory cytokines, including interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (i.e., TNF-α), and strongly inhibited macrophage infiltration in inflamed psoriatic skin. SHK impacted HaCaT cells (a human keratinocyte cell line) viability by enhancing intracellular and mitochondrial ferrous and lipid peroxidation levels by regulating expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear receptor coactivator 4 (NCOA4) and glutathione peroxidase 4 (GPX4) which could be reversed by iron chelating agent. and in psoriatic dermatitis. However, this study found the reversing capability of low dose SHK on LPS inhibited GPX4 and Nrf2 expression, which was identity to that in psoriatic dermatitis. To conclude, SHK inhibited ferroptosis in psoriatic skin by reducing inflammation, ameliorating oxidative stress and iron accumulation. Nrf2 and GPX4 might be the two major targets of SHK in psoriatic skin lesion. Our study highly lighted the basic biological mechanism of SHK on ferroptosis regulation.