OASL activates MAPK to drive psoriatic pathogenesis: Astilbin targeting this axis improves metabolic-inflammation crosstalk.

AIMS: This study aimed to elucidate the role of oligoadenylate synthase-like protein (OASL) as a pivotal regulator integrating keratinocyte hyperproliferation, inflammation, and lipid metabolic dysregulation in psoriasis pathogenesis.

MATERIALS AND

METHODS

Clinical analyses compared epidermal OASL expression levels between psoriasis patients and healthy individuals. Functional studies in HaCaT cells employed OASL knockdown and overexpression to assess effects on proliferation, inflammatory responses, and lipid metabolism. The JAK1-STAT1-OASL regulatory axis was investigated using the JAK1 inhibitor Upadacitinib. The natural flavonoid Astilbin was screened as an OASL inhibitor, and its therapeutic efficacy was evaluated in imiquimod-induced psoriatic mice.

KEY FINDINGS: OASL was significantly upregulated in psoriatic epidermis. Knockdown of OASL suppressed keratinocyte proliferation and inflammation, while its overexpression promoted hyperproliferation, inflammation, and lipid metabolic dysregulation via p38 MAPK pathway activation. Mechanistically, Upadacitinib reduced OASL expression by inhibiting STAT1, confirming the JAK1-STAT1-OASL axis. Astilbin markedly alleviated imiquimod-induced psoriasiform dermatitis in mice.

SIGNIFICANCE: This study reveals OASL's pivotal regulatory role in psoriasis and its associated pathways, providing novel therapeutic targets and a potential natural drug candidate. These findings establish a theoretical foundation for developing multi-targeted strategies against psoriasis.