Glucocorticoid-like pathogenic mechanisms of fipronil metabolites and parthenolide-based intervention strategies

Fipronil (FIP), a widely used phenylpyrazole insecticide, biotransforms into metabolites (FIP-desulfinyl, FIP-sulfone, FIP-sulfide) with enhanced toxicity, persistence, and bioaccumulation potential that pose substantial human health risks. However, their hepatotoxic mechanisms and targeted interventions remain poorly elucidated. This study clarifies FIP metabolites' hepatic pathogenic effects and identifies mitigation strategies. Using mouse primary hepatocytes (MPHs) as an in vitro hepatic model, we combined transcriptomic profiling, Connectivity Map (CMap) analysis, molecular docking, molecular dynamics simulations, and functional validation assays to systematically investigate the mechanisms and intervention targets of FIP metabolite-induced hepatotoxicity. High-throughput transcriptomics showed FIP metabolites induce dexamethasone (DEX)-like phenotypes with enhanced gluconeogenesis and suppressed innate immunity in MPHs. CMap screening identified the natural phytochemical parthenolide (PTL) as a modulator reversing these effects. Mechanistically, molecular docking, molecular dynamics simulations, and functional assays confirmed the androgen receptor (AR) as a common direct target. Importantly, FIP metabolites stabilize AR and promote its accumulation, while PTL competitively binds AR with higher affinity, accelerates its degradation, and abrogates FIP metabolites' detrimental effects. Functionally, PTL dose-dependently inhibits FIP metabolites-induced G6pc upregulation and glucose output, and restores Isg15 mRNA expression and IFN-β levels in MPHs. Collectively, FIP metabolites act as environmental endocrine disruptors via AR stabilization, inducing DEX-like metabolic and immunological dysfunctions. PTL is a promising targeted agent for mitigating FIP metabolites-induced hepatotoxicity, offering insights into FIP metabolites' toxicity mechanisms and related health risk interventions.