Abstract / Summary
Abstract PARP2 is a poly(ADP‑ribose) polymerase with recognized roles in lipid and steroid metabolism in several tissues, but its function in sebocytes has not been defined. In this study, we investigated how PARP2 affects sebocyte lipid metabolism and examined its relevance in skin diseases associated with sebaceous lipid dysregulation. PARP2 deletion in human SZ95 sebocytes resulted in broad transcriptional and lipidomic remodeling, with induction of cholesterol and membrane lipid-associated pathways and higher lipid droplet content. PARP2-deficient sebocytes showed enhanced autophagy, cell death and increased mitochondrial oxidative capacity, consistent with a more advanced differentiation state with altered lipidome. Genes involved in androgen biosynthesis and androgen receptor-linked lipid metabolism were upregulated, and PARP2‑deficient sebocytes produced higher levels of androstenedione and 5α-dihydrotestosterone. Analyses of human skin transcriptomic datasets showed reduced PARP2 expression and altered associations between PARP2 expression and androgen pathway genes in atopic dermatitis, a type 2 inflammatory skin disease in which Th2-driven lipid abnormalities have been linked to altered sebocyte androgen metabolism. In line with this, PARP2 expression was modulated by Th2-type cytokines in sebocytes. In a murine atopic dermatitis model, Parp2 −/− mice showed visually more pronounced skin lesions and induction of sebaceous and androgen-related transcripts in bulk skin. Together, these findings identify PARP2 as a regulator of sebocyte lipid and androgen metabolism and suggest that its dysregulation may contribute to lipid alterations in atopic dermatitis.