Transcriptomic and Metabolomic Analysis Reveals That Polystyrene Microplastics Exacerbate Cadmium-Induced Liver Damage in Mice Associated with AMPK-FOXO-Mediated Energy Metabolism Dysregulation

Microplastics (MPs) can adsorb and transport heavy metals, but their influence on cadmium (Cd)-induced hepatotoxicity in mammals remains unclear. Forty-eight male Kunming mice were assigned to control, Cd, MP, and Cd + MP groups and exposed by oral gavage for 42 days. Growth performance, liver injury, oxidative stress, and inflammation were assessed, and transcriptomic and metabolomic analyses were integrated with qPCR, mitochondrial DNA (mtDNA) copy number, and ATP measurements. Compared with Cd alone, combined exposure resulted in greater reductions in body weight gain, the liver index, and antioxidant enzyme activities, together with more severe hepatic lesions and higher levels of liver injury markers and inflammatory cytokines. Co-exposure also induced broader transcriptional and metabolic disturbances than Cd alone. Integrated omics analyses converged on the dysregulation of AMPK–FOXO signaling and related energy metabolic processes. qPCR confirmed more pronounced alterations in pathway-related genes after co-exposure, while reductions in mtDNA copy number and ATP content indicated aggravated mitochondrial dysfunction and impaired energy metabolism. Collectively, these results demonstrate that MPs exacerbate Cd-induced liver injury and suggest that disruption of AMPK–FOXO-associated energy metabolism is a key molecular feature underlying the enhanced hepatotoxicity observed under combined exposure.