Imidacloprid exposure at population-relevant doses induces hepatic lipid dysregulation: Exploring the role of cGAS-STING pathway-mediated hepatocyte senescence

Pesticide contamination poses a substantial threat to human health. Existing evidence has linked exposure to imidacloprid (IMI) with lipid metabolism disorders. Nevertheless, the mechanisms mediating IMI-induced aberrations in hepatic lipid metabolism and hepatocyte senescence remain incompletely elucidated-particularly the long-term impact effects of exposure at human-relevant doses, which are even less well characterized. To fill this research gap, we conducted a 24-week drinking water exposure experiment in mice using human-relevant doses of IMI (0, 0.015 μg/mL, 0.52 μg/mL, 0.033 mg/mL) to investigate the resulting hepatic lipid metabolism abnormalities and the regulatory role of hepatocyte senescence in this pathological process. Toxicological analyses showed that IMI exposure led to liver function impairment and histopathological changes in mice, induced abnormal hepatic lipid metabolism (p < 0.05), and upregulated the expression of senescence-associated proteins in mice (p < 0.05). Mechanistic investigations further revealed that the cGAS-STING pathway may mediate hepatocyte senescence, and inhibition of this pathway in HepG2 cells markedly alleviated cellular lipid metabolic disorders and senescence (p < 0.05). The findings of this study demonstrate that IMI exhibits chronic hepatotoxicity at human-relevant exposure levels, emphasizing an urgent need for additional toxicological investigations based on human-relevant exposure levels to comprehensively evaluate the toxicity profile of neonicotinoids.