Dihydroartemisinin Targets the NFIC/FBN1 Cascade to Enhance Wound Healing in Chronic Skin Ulcer by Inhibiting Fibroblast Ferroptosis

Dysfunction of fibroblasts contributes to a pathological state to delay wound repair in chronic skin ulcer (CSU). Dihydroartemisinin (DHA), a derivative of artemisinin, has a therapeutic potential in diverse diseases owing to multiple pharmacological effects. However, no attempt was made to evaluate the function of DHA in CSU. Human dermal fibroblasts were isolated from the peripheral ulcerative tissues in CSU patients (uHFBs) and normal skins (nHFBs). Cell migration, proliferation, apoptosis, and ability were detected. Ferroptosis was evaluated by detecting Fe²⁺, iron and ROS contents. Immunoblot and quantitative PCR analyses were performed to quantify expression. The NFIC/FBN1 binding relationship was verified by luciferase reporter assay. The CSU mouse model was established, and histology and Masson's staining was used to analyze DHA efficacy. DHA increased NFIC expression in uHFBs. DHA accelerated cell proliferation and migration and impeded ferroptosis in uHFBs, which could be partially counteracted by NFIC reduction. Mechanistically, NFIC transcriptionally elevated FBN1 expression, and DHA increased FBN1 expression by NFIC. NFIC increase enhanced uHFB proliferation and migration and suppressed ferroptosis, which could be abrogated by FBN1 downregulation. Moreover, DHA improved wound repair in CSU mice by upregulating NFIC and FBN1. Additionally, NFIC and FBN1 were underexpressed in uHFBs versus nHFBs. Our findings indicate that DHA has the efficacy to improve wound repair in CSU mice and upgrades skin fibroblast function via the NFIC/FBN1 cascade. DHA may be a novel drug for CSU treatment.