GLUT1 exacerbates trophoblast ferroptosis by modulating AMPK/ACC mediated lipid metabolism and promotes gestational diabetes mellitus associated fetal growth restriction

Background: Gestational diabetes mellitus (GDM) is associated with a range of fetal complications, including macrosomia and fetal growth restriction (FGR). Infants born to mothers with GDM and FGR are at an increased risk of developing adult-onset obesity and related metabolic disorders. However, the underlying mechanisms driving GDM-associated FGR remain poorly understood.
Methods: We examined placental tissue from GDM patients with FGR for markers of ferroptosis and GLUT1 expression. High glucose conditions were simulated by adding varying concentrations of D-glucose to the culture medium of the 1640 cell line. Ferroptosis sensitivity in trophoblast cells was assessed using RSL3. GLUT1 expression was inhibited using siRNA or the GLUT1 inhibitor WZB117 to evaluate its role in ferroptosis modulation in the HTR8/SVneo cell line. Mechanistic studies focused on the impact of GLUT1 inhibition on AMPK and ACC phosphorylation, key regulators of lipid metabolism and ferroptosis. In murine models, streptozotocin (STZ)-induced GDM was treated with WZB117 and the ferroptosis inhibitor Liproxstatin-1 (Lip-1). Finally, levels of AMPK and ACC phosphorylation were assessed in placental samples from GDM patients.
Results: Placentas from GDM patients with FGR exhibited signs of ferroptosis and upregulated GLUT1 expression. In cell models, high glucose conditions enhanced ferroptosis sensitivity in trophoblast cells and induced GLUT1 expression. Notably, inhibition of GLUT1 significantly reduced ferroptosis in trophoblast cells under high glucose conditions. Mechanistically, elevated GLUT1 expression suppressed AMPK phosphorylation and reduced ACC phosphorylation, which in turn promoted lipid synthesis and facilitated ferroptosis. In STZ-induced GDM mice, treatment with either WZB117 (GLUT1 inhibitor) or Lip-1 (ferroptosis inhibitor) mitigated the FGR phenotype. In vivo, increased GLUT1 expression correlated with higher levels of ferroptosis markers, reduced AMPK/ACC phosphorylation, and altered lipid metabolism, which likely contributed to the observed FGR phenotype. Additionally, placental samples from GDM patients showed decreased AMPK and ACC phosphorylation.
Conclusions: Our findings suggest that ferroptosis plays a key role in GDM-associated FGR. Dysregulation of the GLUT1-AMPK-ACC axis may contribute to the pathogenesis of GDM-associated FGR, highlighting potential therapeutic targets for managing this condition in clinical settings.