Quercetin attenuates polyethylene terephthalate nanoplastic-induced malignant phenotypes linked to APOE stabilization and lipid metabolic reprogramming in prostate cancer.

Micro- and nanoplastics (MNPs) are emerging environmental contaminants with increasing evidence of biological activity in mammalian systems. However, the molecular mechanisms by which chronic polyethylene terephthalate nanoplastic (PET-NPs) exposure promotes prostate cancer progression, and whether this process can be attenuated by quercetin, remain poorly understood. DU-145 and LNCaP cells were subjected to repeated PET-NPs exposure and analyzed using functional assays, DIA proteomics, protein-stability and ubiquitination assays, APOE loss- and gain-of-function experiments, and xenograft models. PET-NPs enhanced proliferation, migration, invasion, intracellular lipid accumulation, and tumor growth. Proteomic analysis highlighted cholesterol metabolism, lipid transport, and PI3K/AKT signaling, leading to prioritization of APOE. PET-NPs increased APOE protein abundance without altering APOE mRNA, prolonged APOE protein stability, and reduced its ubiquitination-dependent proteasomal turnover. APOE knockdown attenuated PET-NPs-induced increases in triglyceride and total cholesterol levels, PIK3CA expression, AKT phosphorylation, proliferation, migration, and invasion, supporting APOE as an important but non-exclusive functional contributor. Quercetin reduced APOE mRNA and protein abundance and suppressed PET-NPs-associated lipid accumulation, PI3K/AKT activation, and malignant phenotypes in vitro. APOE overexpression partially restored PIK3CA expression, AKT phosphorylation, total cholesterol levels, EdU incorporation, invasion, and migration in both DU-145 and LNCaP cells under PET-NPs plus quercetin treatment, whereas the restoration of triglyceride levels reached statistical significance only in LNCaP cells. In vivo, quercetin attenuated PET-NPs-associated subcutaneous and orthotopic tumor progression and reduced APOE, p-AKT, PLIN2, Ki-67, and MMP2 staining. These findings indicate that APOE contributes to, but does not fully account for, the inhibitory effects of quercetin.