Interleukin-17 orchestrates psoriasis pathogenesis through canonical and noncanonical signaling pathways and emerging therapeutics

A BSTRACT Psoriasis is a chronic immune-mediated skin disorder, characterized by keratinocyte hyperproliferation and inflammatory cell infiltration. The interleukin-23 (IL-23)/IL-17 axis has been established as a central driver of disease pathogenesis, and biologics targeting this pathway has significantly improved clinical outcomes. However, accumulating evidence indicates that residual molecular alterations persist despite clinical remission, suggesting that immune-targeted therapies may not fully address keratinocyte-intrinsic dysregulation. Canonical IL-17 signaling primarily mediates inflammatory responses through the induction of cytokines and chemokines that promote immune cell recruitment, whereas noncanonical IL-17 signaling regulates keratinocyte-intrinsic processes, including metabolic reprogramming, lipid homeostasis, cellular proliferation, and differentiation. Recent studies have highlighted that pyruvate kinase M2 (PKM2)-mediated glycolysis, lipid metabolic remodeling, and Hippo–YAP signaling are the key components of these noncanonical pathways and contribute to sustained epidermal abnormalities and disease progression. This review summarizes the roles of canonical and noncanonical IL-17 signaling in psoriasis, with particular emphasis on keratinocyte biology and the emerging significance of noncanonical signaling in disease persistence. We further discuss emerging therapeutic strategies targeting these pathways. Targeting keratinocyte-intrinsic noncanonical IL-17 signaling may complement current biologic therapies by addressing pathogenic mechanisms that are not fully corrected by immune-directed treatments, thereby providing a more comprehensive approach to disease control and long-term remission.