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

## TL;DR

Brusatol treats psoriasis-related lipid issues by targeting IL-1β and restoring AMPK function, which helps balance lipid levels and reduce inflammation.

## Contribution

The study reveals a novel IL-1β–AMPK interaction and shows brusatol disrupts it to treat psoriatic dyslipidemia.

## Key findings

- Brusatol reduces inflammation and proliferation in TNF-α-stimulated HaCaT cells.
- It ameliorates skin lesions and lipid imbalances in psoriatic mice without toxicity.
- Brusatol binds to IL-1β, disrupting its interaction with AMPK to restore lipid homeostasis.

## Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13020-025-01287-8.

Brusatol dose-dependently suppresses proliferation and inflammation in TNF-α-induced HaCaT keratinocytes.Brusatol ameliorates skin lesions and systemic dyslipidemia in IMQ-induced mice models without inducing visceral organ toxicity.Brusatol ameliorates psoriatic dyslipidemia through direct binding to IL-1β, which disrupts a novel IL-1β–AMPK interaction and restores AMPK-mediated lipid homeostasis.

Brusatol dose-dependently suppresses proliferation and inflammation in TNF-α-induced HaCaT keratinocytes.

Brusatol ameliorates skin lesions and systemic dyslipidemia in IMQ-induced mice models without inducing visceral organ toxicity.

Brusatol ameliorates psoriatic dyslipidemia through direct binding to IL-1β, which disrupts a novel IL-1β–AMPK interaction and restores AMPK-mediated lipid homeostasis.

The online version contains supplementary material available at 10.1186/s13020-025-01287-8.