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.