Hypothalamic FTO-IGF2BP2-mediated m6A regulation of ANXA2: A novel axis preventing HS-induced sperm motility decline

Global heat stress (HS) is an increasingly pervasive environmental threat to male fertility, yet the central neuroendocrine mechanisms mediating this effect remain incompletely understood. Here, using complementary murine and porcine models, we demonstrate that HS caused a marked reduction in hypothalamic expression of N⁶-methyladenosine (m⁶A) demethylase FTO, leading to widespread m⁶A hypermethylation, astrocytic and microglial activation, disruption of blood-brain barrier (BBB) integrity, and suppression of GnRH, LH, FSH, and testosterone secretion. Lentiviral restoration of FTO in the third ventricle reestablished m⁶A homeostasis, attenuated glial inflammatory responses, preserved vascular barrier function, and normalized neuroendocrine hormone levels. These central corrections were associated with improved testicular histology, reduced oxidative stress and apoptotic markers, and enhanced sperm curvilinear and straight-line velocities. Mechanistically, FTO demethylated Anxa2 mRNA, facilitating IGF2BP2 recognition and preventing ANXA2 protein overaccumulation, thereby restoring hypothalamic lipid metabolic homeostasis and reducing proinflammatory cytokine production. Collectively, our results defined a conserved hypothalamic FTO-IGF2BP2-ANXA2 epitranscriptomic axis that coupled central neuroinflammation to peripheral redox as well as reproductive homeostasis, and provides a molecular rationale for neuroendocrine-targeted interventions against HS-induced male infertility.