FGF12, a FoxO1-downregulated gene, promotes the survival of trophoblast cells in gestational diabetes mellitus: a preliminary study

Abstract

OBJECTIVES: Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and fetal outcomes. Although the prevalence of GDM is high, the molecular mechanisms involved in GDM-related placental dysfunction remain poorly understood. This study aimed to investigate the roles of Forkhead box O1 (FoxO1) and fibroblast growth factor 12 (FGF12; a non-FGF receptor) in regulating trophoblast survival under GDM conditions. MATERIAL AND METHODS: Placental tissue from women with GDM and matched non-GDM controls were collected to assess FGF12 expression. HTR8/SVneo trophoblast cells under high-glucose conditions were used to assess cellular functional assays, including proliferation, migration, and apoptosis, following FGF12 knockdown or overexpression. RESULTS: The level of FGF12 was significantly attenuated in placental tissues from GDM cases. Silencing FGF12 decreased trophoblast growth and migration, and increased apoptosis induced by high glucose, while FGF12 overexpression reversed these effects. Mechanistically, FoxO1 directly bound to the FGF12 promoter, downregulated its expression. In placental samples from GDM pregnancies, FoxO1 expression was negatively correlated with FGF12 levels. Furthermore, FoxO1 inhibited trophoblast proliferation and migration, while FGF12 overexpression partially rescued the inhibitory effects of FoxO1. CONCLUSIONS: These findings suggest that the FoxO1/FGF12 pathway may contribute to impaired trophoblast function in GDM. This study provides preliminary evidence for a regulatable molecular pathway involved in GDM-associated placental dysfunction; however, further validation in larger cohorts and physiologically relevant models is required before clinical applications can be applied.