Integrated bioinformatics and experimental validation reveal lucanthone as a promising therapeutic agent targeting core genes in psoriasis.

Psoriasis is an immune-mediated chronic inflammatory skin disease driven by epidermal hyperproliferation and cutaneous immune dysregulation, yet lacks reliable diagnostic biomarkers. Here, we identified 14 core genes with excellent diagnostic value (AUC = 0.996), which were abnormally upregulated in psoriatic lesions, specifically expressed in keratinocytes, and closely correlated with pathogenic immune infiltration. Among these, CCNA2 was confirmed to causally drive psoriasis pathogenesis. Functional drug enrichment analysis of core intersecting genes identified lucanthone as a potential therapeutic agent. Mechanistically, lucanthone stably targeted AURKA and G2/M checkpoint hub genes, suppressing keratinocyte proliferation while promoting apoptosis. Concurrently, it mitigated keratinocyte-derived inflammation, blocked pathogenic Th17 and γδ T17 cell activation, and significantly ameliorated psoriasiform dermatitis. Collectively, these findings establish a high-confidence gene signature for psoriasis diagnosis and pathogenesis research, and position lucanthone as a promising repurposed therapeutic candidate for clinical translation.