Glucocorticoid receptor-targeting antagomirs alleviates AFB1-induced hepatotoxicity in mice

Aflatoxin B1 (AFB1) exhibits hepatotoxic properties in both humans and animals. Contradictory findings regarding corticosterone suggest that it may either aggravate AFB1 toxicity or reduce its Lethal Dose 50 % (LD50), potentially through the role of the glucocorticoid receptor (GR). Additionally, microRNAs (miRNAs) are known to modulate the toxic effects of AFB1. Nevertheless, whether the modulation of GR-targeting miRNAs can alleviate AFB1-induced hepatotoxicity has not been thoroughly investigated. This study examined the expression of GR and its associated microRNAs in AFB1-induced hepatotoxicity in mice, using GR-targeting antagomirs to mitigate AFB1 toxicity. AFB1 exposure elicited liver inflammation and oxidative stress in mice, while also reducing detoxification capacity. Notably, a decrease in GR protein expression was observed in liver tissue and hepatocytes. Additionally, miR141-3p, miR200a-3p, miR384-5p, miR183-5p, miR181a-5p, and miR181b-5p were upregulated and identified as regulators of GR expression. AFB1 induced cytotoxicity in AML12 cells, as evidenced by decreased GR protein levels and increased expression of miR141-3p, miR200a-3p, and miR495-3p. Inhibition of miR141/200a/495-3p reduced AFB1-induced cytotoxicity in AML12 cells. Furthermore, GR-targeting antagomirs (antagomir141/200a/495-3p) alleviated AFB1-induced hepatotoxicity in mice. This study highlights potential therapeutic targets for AFB1-induced liver diseases and offers new insights into strategies to mitigate the harmful effects of aflatoxin exposure.