Dictamnine inhibited keratinocyte hyperproliferation and alleviated psoriasis-like dermatitis via blocking HIF1A-mediated ferroptotic pathway

Ethnopharmacological relevance Psoriasis is an immune-mediated genetic skin disease, which is characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes. Recently, there are not any cures for psoriasis because of the limited availability of safe and effective medications. Dictamni Cortex is the root bark of Dictamnus dasycarpus Turcz. And exhibits anti-inflammatory, antibacterial, hepatoprotective and anticancer activities. It is widely used for preventing various bone and skin diseases, including rheumatoid arthritis, psoriasis, eczema and impetigo. However, the active compounds responsible for treating psoriasis in the herb remain unknown. Aim of the study To investigate the inhibitory effects of active compounds in the herb against the hyperproliferation of human HaCaT keratinocytes in vitro and imiquimod (IMQ)-induced psoriasis-like dermatitis in mice. Materials and methods The effects of each active compound in the herb against the proliferation, apoptosis, migration, and invasion of HaCaT cells were analyzed by MTT, flow cytometry, and Transwell assays, respectively. The profiles of differentially expressed mRNAs between model group and dictamnine (DIC)-treated group were compared by transcriptome sequencing. The levels of inflammatory cytokines and chemokines in the mediums and skin tissues were measured by ELISA assay. IMQ-induced psoriasis-like dermatitis in mice were evaluated by HE stain and immunohistochemical analysis. The expressions of HIF1A and its downstream were measured by western blotting analysis. Results Compared with the methanol extract and other active compounds, DIC displayed the strongest inhibition on the hyperproliferation of KGF-stimulated HaCaT cells. DIC remarkably inhibited the proliferation, migration and invasion of HaCaT cells in a concentration-dependent manner. It also reduced the production of IL-6, IL-23 and VEGF, the activities of GSH and SOD, and the expressions of K17 , CCL20 and CXCL2 mRNAs, but elevated the levels of ROS, Fe 2+ and MDA in KGF-exposed HaCaT cells. Moreover, DIC significantly mitigated imiquimod-induced psoriasis-like dermatitis in mice. Mechanically, DIC promoted the ferroptosis of HaCaT cells via targeting HIF1A, thereby suppressing the nuclear translocation of HIF1A and its dowmstream GPX4 and SLC7A11. These benefits of DIC treatment could be reversed by ferroptotic inhibitor Ferrostatin-1 and HIF1A stabilizer DMOG. Conclusions DIC ameliorated psoriasis in part by triggering HIF1A-dependent ferroptosis in keratinocytes. It suggested that DIC was the main active compound in D. Cortex and has therapeutic potential for the treatment of psoriasis.