Zearalenone suppresses pituitary follicle-stimulating hormone synthesis via ALKBH5-YTHDF2-SMAD4 axis

Zearalenone (ZEA) is a mycotoxin derived from contaminated feed and causes endocrine disruption, posing a significant environmental threat to reproductive health. In this study, we investigated the molecular mechanism through which ZEA regulates pituitary gonadotropin synthesis via N6‑methyladenosine (m⁶A) modification. We demonstrated that ZEA downregulates alkB homolog 5, RNA demethylase (ALKBH5) in the pituitary by promoting its ubiquitination and subsequent protein degradation. This downregulation increases m⁶A modification of SMAD family member 4 (SMAD4) mRNA, which in turn recruits the m⁶A reader YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) to promote SMAD4 mRNA degradation. Consequently, reduced SMAD4 protein levels ultimately suppress follicle-stimulating hormone (FSH) synthesis in gonadotrope cells. Collectively, these findings link m⁶A modification to the endocrine function of gonadotropes via the ALKBH5-YTHDF2-SMAD4 axis, offering mechanistic insights and potential targets for counteracting ZEA-induced reproductive toxicity.