Isolinderalactone targets TNF-α/STAT3 inflammatory pathways to attenuate psoriasis-like dermatitis.

Abstract

BACKGROUND: Given the proinflammatory cascade elicited by tumor necrosis factor-α (TNF-α) in psoriasis, multiple TNF-α-targeted biologics have been developed for psoriasis treatment. Although systemic macromolecular biologics are widely used, a crucial therapeutic gap remains for mild-to-moderate psoriasis, underscoring an unmet need for more effective topical drugs suppressing TNF-induced inflammatory signaling. OBJECTIVE: To identify a novel potent natural small-molecule drug suppressing TNF-induced inflammatory signaling and elucidate its therapeutic mechanism in psoriasis. METHODS: First, candidate small-molecule drugs were screened out through a high-throughput screening platform. Next, the therapeutic effect of Isolinderalactone was evaluated through topical application in the imiquimod (IMQ)-induced psoriasis-like mouse model. Subsequently, RNA sequencing (RNA-seq) analysis of TNF-α-stimulated HaCaT cells and epidermis of IMQ-treated mice identified key transcriptomic alterations induced by Isolinderalactone treatment. Finally, anti-psoriasis effects and underlying mechanisms of Isolinderalactone were verified in both in vivo and in vitro experiments. RESULTS: Isolinderalactone was identified as a potent drug suppressing TNF-related signaling with low cytotoxicity. Topical application of Isolinderalactone significantly alleviated IMQ-induced psoriasis-like dermatitis. Conjoint analysis of RNA-seq for TNF-α-stimulated HaCaT cells and epidermis from lesions of IMQ-treated mice revealed Isolinderalactone downregulated the expression of TNF-α, interleukin-17 (IL-17) and S100-related inflammatory factors in epidermal keratinocytes. Mechanistically, Isolinderalactone significantly inhibited the TNF-α/STAT3 inflammatory pathways in epidermal keratinocytes and exerted an anti-inflammatory effect. CONCLUSION: Isolinderalactone exhibits anti-inflammatory activity through multiple mechanisms, highlighting the potential of topical Isolinderalactone therapy for mild-to-moderate psoriasis.