Astragaloside IV regulates FOXM1 deubiquitination to ameliorate trophoblast damage caused by high glucose

Background: Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy that poses significant risks to both the pregnant woman and her fetus. Astragaloside IV (Ast IV) belongs to the class of triterpenoid saponins and exhibits important physiological roles in various aspects, including antidiabetic, antioxidant, and Antiviral effects. The main objective of this study is to investigate the effects of Ast IV on trophoblast damage caused by high glucose (HG) and its underlying mechanism of action.

Methods: Cell viability was determined by the CCK8 assay. The levels of oxidative stress in cells were determined by Lactate Dehydrogenase (LDH), malondialdehyde (MDA), and Reactive Oxygen Species (ROS) kits. Ferroptosis in cells was assessed by the iron content kit. Gene expression levels were detected by real-time quantitative Reverse transcription PCR (qRT-PCR) and western blot. The protein stability of Forkhead box protein M1 (FOXM1) was determined by the cycloheximide (CHX) assay. The ubiquitination level of FOXM1 was detected by the immunoprecipitation assay.

Results: Ast IV alleviated the inhibitory effect of HG on the proliferation of HTR-8/SVneo cells and reduced HG-induced oxidative stress and Ferroptosis. Ast IV was able to decrease the ubiquitination of FOXM1, thereby ensuring the stability of its expression. The overexpression of FOXM1 significantly mitigated the inhibitory effect of HG on the viability of HTR-8/SVneo cells and concurrently decreased the occurrence of HG-induced oxidative stress and Ferroptosis processes. Conversely, knockdown of FOXM1 diminished the protective effect of Ast IV on HTR-8/SVneo cells.

Conclusions: Ast IV ameliorates HG-induced trophoblast injury by modulating deubiquitination of FOXM1, which provides a new insight into the treatment of GDM.

Astragaloside IV; Deubiquitination; Forkhead box protein M1; Gestational diabetes mellitus; Hyperglycemic induction.