Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis

Psoriasis is an autoimmune skin disease, and its pathogenesis remains incompletely understood. As central drivers of psoriasis pathogenesis that bridge innate and adaptive immunity, macrophages are known to be modulated in their function by insulin-induced gene 1 (INSIG1), a regulator of cholesterol synthesis. Bioinformatic analysis of human psoriatic lesions reveals a significant negative correlation between INSIG1 expression and pro-inflammatory cytokine levels (IL-23, IL-17A). Single-cell RNA sequencing (scRNA-seq) and immunofluorescence confirm significantly reduced INSIG1 expression specifically in macrophages from psoriatic skin. In vivo, myeloid-specific Insig1 deficiency exacerbates imiquimod (IMQ)-induced psoriasiform dermatitis, characterized by increased epidermal thickening and immune infiltration. By activating sterol regulatory element-binding protein 2 (SREBP2), INSIG1 deficiency leads to the transcriptional upregulation of STAT1, which drives M1 macrophage polarization and ultimately amplifies psoriatic inflammation. This study reveals an important role of macrophage INSIG1 in regulating inflammatory responses and lipid metabolism, providing insight into the pathogenesis of psoriasis and potential therapeutic targets.