Network pharmacology-guided discovery of avicularin from Euphorbia humifusa Willd. targeting IL-17 signaling in psoriasis

Despite therapeutic advances, long-term psoriasis management remains challenged by cost, immunogenicity, and administration barriers. Although the anti-inflammatory properties of avicularin (AL) are recognized, its direct targeting of IL-17RA and its therapeutic efficacy in psoriasis remain unreported. Here, we established the efficacy of Euphorbia humifusa Willd. (EH) in a psoriasis mouse model, then used an integrated strategy combining network pharmacology, RNA-seq, and surface plasmon resonance-mass spectrometry (SPR-MS) to assess its pharmacodynamic material basis. This systematic approach identified the IL-17 pathway as the primary mechanism, and IL-6, CXCL10, and IL-17RA as key targets. On the basis of these key targets, SPR-MS screened seven candidate compounds from EH, among which AL was confirmed as a key IL-17RA-targeting bioactive compound. Subsequent validation demonstrated that AL dose-dependently ameliorated psoriatic lesions and downregulated key IL-17 pathway effectors, including IL-17RA, IL-6, and CXCL10 ( p < 0.05). Direct binding between AL and IL-17RA was subsequently confirmed through bio-layer interferometry, SPR-MS re-screening, and molecular docking. Our findings not only establish AL as a promising oral IL-17RA-targeted agent but also delineate a robust strategy that may aid in the systematic discovery of active natural compounds.