Zearalenone-induced hepatotoxicity: Underlying mechanisms and genistein-mediated preventive effects

Zearalenone (ZEA), a mycotoxin produced by Fusarium fungi, has drawn significant attention due to its multi-organ toxicity. To explore the molecular mechanisms of ZEA-induced hepatotoxicity and identify effective intervention strategies, this study identified key targets associated with ZEA-induced hepatotoxicity by screening public databases. Further construction of a protein interaction network revealed five crucial targets: TP53, STAT3, HSP90AA1, ESR1, and PPARG. Moreover, genistein (GEN) was identified from the TCMSP database as a compound capable of simultaneously targeting these targets. Molecular docking results indicated that GEN exhibits strong binding affinity with the five targets (all binding energies <0 kcal/mol). To validate hepatotoxicity mediated by ZEA and intervention mechanisms of GEN, ZEA exposure and ZEA + GEN treated mouse models were conducted. The results exhibited that exposure to ZEA led to increased liver weight and liver coefficient as well as abnormal changes in typical hepatotoxicity indicators in mice, while GEN can alleviate the aforementioned changes. Furthermore, results from quantitative RT-PCR and Western blot indicated that hepatic Hsp90aa1 and HSP90α (the protein encoded by the Hsp90aa1 gene) expression was significantly upregulated by ZEA but significantly downregulated after GEN supplementation. In conclusion, HSP90α may be a key regulatory node in GEN treatment of hepatotoxicity caused by ZEA.