Gut microbiota remodeling correlates with pentose phosphate pathway activation and steroid hormone biosynthesis dysregulation in polystyrene nanoplastic-induced hepatic lipotoxicity.

Polystyrene nanoplastics (PS-NPs) have been detected in human tissues, but the systemic consequences of chronic oral exposure remain unclear. Female Sprague-Dawley rats received environmentally relevant PS-NP concentrations of 5 or 50 mg/L in drinking water for 42 days. Gut-liver-endocrine interactions were assessed by 16S rRNA sequencing, shotgun metagenomics, fecal metabolomics, hepatic transcriptomics, and biochemical validation of selected nodes. PS-NP exposure caused notable dysregulation of serum and hepatic lipids and produced histopathological damage in the liver. The exposure was also associated with gut dysbiosis dominated by Bacteroidia, along with hepatic glucose-6-phosphate dehydrogenase (G6PD) upregulation and pentose phosphate pathway (PPP) activation, as well as NADPH accumulation. Low-dose exposure was associated with adaptive redox response (elevated hepatic superoxide dismutase (SOD)) and lipid clearance signatures, whereas high-dose exposure correlated with glutathione peroxidase (GSH-PX) depletion, elevated 8-iso-prostaglandin (8-iso-PG), and transcriptomic evidence of mitochondrial impairment and ferroptosis vulnerability. Steroid hormone biosynthesis (SHB) disruption-declining estradiol and rising cortisol-was observed across both doses, with ovarian Cyp19a1/Cyp11a1 downregulation at low dose and additional adrenal Cyp21a2 upregulation at high dose. Multi-omics integration linked Bacteroidia enrichment to the PPP intermediate deoxyribose 5-phosphate and estrogen metabolites. Collectively, these findings outline a Gut Microbiota-PPP-SHB (GMPS) axis as a candidate integrative framework for understanding PS-NP-associated hepatic lipotoxicity. This work offers an integrative resource that identifies candidate pathways and testable hypotheses for future investigation of metabolic risks from chronic nanoplastic exposure.