Zearalenone promotes hepatic lipid accumulation via EGFR-HSP90 complex stabilization.

Zearalenone (ZEA), a widespread foodborne mycotoxin, has been implicated in metabolic dysfunction-associated fatty liver disease (MAFLD), although its direct hepatic targets and mechanisms remain unclear. This study aimed to identify the molecular target of ZEA and elucidate its role in hepatic lipid dysregulation. Using drug affinity responsive target stability, network toxicology, molecular docking, cellular thermal shift assay, microscale thermophoresis, and molecular dynamics simulations, epidermal growth factor receptor (EGFR) was identified as a direct binding target of ZEA. In C57BL/6J mice (0.5 mg/kg·body weight, 5-day oral gavage) and HepG2 cells (0-20 μM ZEA), ZEA activated EGFR signaling by enhancing transcription and stabilizing EGFR protein via promotion of the EGFR-HSP90 complex. EGFR activation promoted proteolytic cleavage and nuclear translocation of SREBP1c, leading to upregulation of lipogenic enzymes (SCD1, ACC, FASN) and exacerbated lipid accumulation, especially under high fatty acid conditions. Artemether (Art), an artemisinin derivative reported to disrupt the EGFR-HSP90 complex and improve hepatic lipid metabolism, was therefore selected as a therapeutic intervention. Art significantly attenuated EGFR expression and downstream lipogenesis by disrupting the EGFR-HSP90 complex, thereby alleviating ZEA-induced lipid deposition. The EGFR inhibitor erlotinib reversed both ZEA-induced lipogenesis and the protective effects of Art, confirming the central role of EGFR signaling. Collectively, ZEA promotes hepatic lipid accumulation via stabilization of the EGFR-HSP90 complex and activation of the EGFR-SREBP1c axis, suggesting EGFR as a potential therapeutic target.