Prednisone combined with dihydroartemisinin inhibits the excessive activation of skin keratinocytes in lupus erythematosus by targeting MAPK14.

BACKGROUND: Systemic lupus erythematosus (SLE) is a highly complex autoimmune disorder that poses considerable treatment challenges. Among them, cutaneous lupus erythematosus (CLE) is one of the most common and earliest clinical symptoms. Dihydroartemisinin (DHA) is a semi-synthetic derivative of artemisinin, which is extracted from the traditional Chinese herb Artemisia annua. Recent studies have suggested that DHA has immunosuppressive effects. This study aims to further explore the role of DHA in SLE-related skin conditions and its effects on keratinocytes (KC). METHODS: A mouse model of SLE was created by inducing the disease with Pristane, and skin damage was assessed using the CLASI scoring system. Histological alterations were analyzed through H&E and Masson staining. IF was used to detect IgG and C3 deposits in the skin tissue, while immunohistochemistry evaluated the expression of K16. An in vitro SLE skin model was developed by exposing mouse keratinocytes to ultraviolet light. Subsequently, cell proliferation was measured using the EDU assay, ROS levels were determined by DCFH-DA fluorescence, cytokine levels were quantified via ELISA, and cell chemotaxis was assessed using a Transwell assay. Previous research has shown that the MAPK signaling pathway plays a role in treating SLE with prednisone and DHA, and further MCODE analysis identified MAPK14 as the key gene within this pathway. RESULTS: The findings demonstrated that combining Prednisone (PDN) with DHA can reduce skin lesions associated with SLE and the abnormal activation of KC in mice. Mechanistically, we discovered that PDN and DHA bind together to suppress inflammatory activation of KC by targeting MAPK14, thereby modulating the Treg/Th17 balance. CONCLUSION: This research highlights the protective role of DHA in SLE-related skin inflammation and offers experimental support for its ability to improve abnormal KC activation via immune regulatory pathways.