Brusatol ameliorates psoriatic dyslipidemia by targeting IL-1β to restore AMPK-mediated lipid homeostasis

BACKGROUND: Psoriasis-associated dyslipidemia presents as a critical comorbidity characterized by a self-perpetuating cycle of metabolic dysfunction and chronic inflammation. Current treatment paradigms lack the capacity to simultaneously modulate these interconnected pathological axes. Here we investigated the efficacy and mechanisms of brusatol (a natural quassinoid derived from Bruceae Fructus) against psoriatic dyslipidemia from the insight of restoring lipid homeostasis. METHODS: The in vitro efficacy of brusatol was assessed in TNF-α-stimulated HaCaT keratinocytes by evaluating proliferation, apoptosis, and inflammatory responses. In vivo, its therapeutic activity and systemic toxicity were examined in an imiquimod-induced psoriatic mouse model using PASI scoring, histopathological analysis, serum biochemical markers (TC, TG, ALT, AST, Cre), inflammatory cytokines (TNF-α, IL-1β, IL-17A), and BBB-chip analysis. Integrated proteomics and lipidomics of skin tissue and serum revealed dysregulated pathways, and subsequent target engagement was confirmed via molecular docking, CETSA, and DARTS. Mechanistic investigations included IL-1β overexpression, Co-IP, GST pull-down and AMPK pathway analysis (Western blot, qPCR) was explored to delineate the regulatory mechanisms. RESULTS: Brusatol dose-dependently suppresses proliferation and inflammatory mediator expression in TNF-α-induced HaCaT keratinocytes, ameliorates skin lesions and systemic dyslipidemia in mice, effectively normalizing serum TC and TG levels without inducing visceral organ toxicity. Further integrated omic analyses and subsequent target validation identified IL-1β as the direct target linking inflammatory signaling and lipid dysregulation. Mechanistic studies uncovered a novel IL-1β-AMPK physical interaction that sequesters AMPK in the cytoplasm. Brusatol disrupts this complex, facilitating AMPK nuclear translocation to suppress lipogenic regulators (SREBP-1c/FASN/ACC1) and potentiate β-oxidation pathways (PPARα/CPT1A), thereby restoring lipid homeostasis. CONCLUSION: Our findings not only establish brusatol as an effective agent for ameliorating psoriatic dyslipidemia, but also unveil a fundamental IL-1β-AMPK interaction that orchestrates inflammation-metabolism crosstalk.