Sanghuangporus sanghuang targets AKT to rescue nanoplastics-induced lipid accumulation and neurotoxicity

BACKGROUND: Nanoplastics, particularly polystyrene nanoplastics (PS-NPs), pose significant health risks by inducing lipid metabolism disorders and neurotoxicity. Current countermeasures remain inadequate against these multifaceted toxicities, necessitating exploration of natural bioactive compounds with multi-target therapeutic potential. PURPOSE: This study aims to evaluate the therapeutic effect and potential mechanism of Sanghuangporus sanghuang ethanol extract (SH) against PS-NPs-induced lipid dysregulation and neurotoxicity. METHODS: Chemical constituents of SH were characterized via UPLC-MS/MS. The ameliorative effects of SH on lipid metabolism disorder and neurotoxicity induced by PS-NPs exposure were preliminarily evaluated using zebrafish and Caenorhabditis elegans models. Network pharmacology identified key targets for SH's lipid-modulating and neuroprotective effects. Mechanisms were elucidated through mRNA expression analysis of relevant genes and validation using specific C. elegans mutant strains. RESULTS: SH exhibited potent antioxidant activity in vitro and in vivo. It significantly ameliorated PS-NPs-induced pathological damage by activating the AKT pathway, enhancing reactive oxygen species (ROS) scavenging, and subsequently attenuating lipid metabolism dysregulation and neurotoxicity. Protocatechuic aldehyde and osmundacetone as main components in SH contributed to AKT pathway activation and also rescued PS-NPs-induced toxicity. These effects were abolished in akt-1 knockout mutants, confirming pathway specificity. CONCLUSION: Our findings reveal SH as a novel dietary intervention counteracting nanoplastics toxicity through AKT-mediated regulation, providing a pharmacological basis for developing S. sanghuang-based functional foods against environmental particle exposure.