Targeting the PCSK9–PR–IL-17 axis for psoriasis therapy

Abstract

Psoriasis is a chronic, immune-mediated inflammatory dermatosis characterized by keratinocyte hyperproliferation and systemic metabolic comorbidities. Although proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established regulator of lipid metabolism, its role in the cutaneous inflammatory microenvironment remains poorly defined. This study investigated the contribution of PCSK9 to psoriatic inflammation and its potential underlying mechanisms. PCSK9 expression was assessed in human psoriatic lesions and an imiquimod (IMQ)-induced mouse model. The effects of pharmacological PCSK9 inhibition with SBC-110736 were evaluated using PASI-like scores and inflammatory cell infiltration. Transcriptomic analysis was performed to identify associated signaling pathways. The relationship between PCSK9 and progesterone receptor (PR) expression in keratinocytes and the effects of the PR agonist progesterone were also examined. PCSK9 expression was significantly upregulated in human psoriatic lesions and in the IMQ-induced mouse model. SBC-110736 attenuated psoriasis-like disease severity, reducing PASI-like scores and infiltration of CD4 + and CD11b + cells. Transcriptomic analysis indicated that PCSK9 inhibition primarily suppressed interleukin-17 (IL-17) signaling while restoring Pgr expression. PCSK9 and PR expression were inversely associated in keratinocytes, suggesting that PCSK9-mediated PR downregulation may exacerbate IL-17-driven inflammation. Progesterone treatment produced similar therapeutic effects to those observed with PCSK9 inhibition. These findings suggest that a PCSK9–PR–IL-17 axis contributes to psoriasis pathogenesis, with PR potentially serving as an endogenous anti-inflammatory brake. Targeting this pathway may offer a strategy to modulate cutaneous inflammation, while its potential effects on related metabolic disturbances warrant further investigation.