Cross-kingdom stress response: Hepatocyte lipid disruption by nanoplastics and plant-derived remediation

Living organisms face chronic exposure to environmentally ubiquitous nanoplastics (NPs), yet several aspects of their impact on human health remain poorly defined. This study investigates the lipid metabolic response of human hepatocytes (HepG2) to prolonged exposure (up to 28 days) in vitro to environmentally relevant concentrations of 500 nm polystyrene NPs (10⁴ and 10⁶ particles/mL). No overt cytotoxicity was observed: Annexin V apoptosis assays were negative, with no morphological changes by light microscopy or FACS; NPs showed no cell association or internalization. However, intracellular lipid content increased significantly by day 5, peaking at day 14 and mirroring transcriptional upregulation of genes involved in lipid metabolism and trafficking. Lipidomic profiling showed progressive remodelling from day 14: saturated fatty acids accumulated while unsaturated fatty acids declined, indicative of stress-induced shifts. This remodelling was accompanied by a stress response at day 7, marked by overexpression of proinflammatory cytokine and ER stress genes. By day 28, total lipids partially declined (suggesting compensatory mechanisms), yet the pathological signature persisted. These findings reveal hepatocyte stress and resilience dynamics under chronic NP insult, predisposing to lipotoxic inflammation. Preliminary results in this underexplored model of chronic in vitro NP exposure suggest promising phytoremediation potential for plant-derived molecules (proanthocyanidins and anthocyanins, low-molecular-weight phenolic amides), bridging plant resilience to animal cells.