Circular RNA HIPK3 facilitates ferroptosis in gestational diabetes mellitus by regulating glutathione peroxidase 4 DNA methylation

Abstract

AbstractBackgroundGestational diabetes mellitus (GDM) is the most frequently occurring complication during pregnancy, with a high prevalence rate. Ferroptosis, a type of iron‐dependent cell death, is closely associated with GDM nosogenesis. The present study aimed to examine the potential role and mechanism of circHIPK3 in GDM.MethodsPlacental tissues, plasma samples, and HTR‐8/SVneo cells were used. A receiver operating characteristic curve was used to analyze the diagnostic value of circHIPK3 in GDM. Actinomycin D and RnaseR were added to identify circHIPK3 characteristics. The expression of circHIPK3, miR‐1278, and DNA methyltransferase 1 (DNMT1) was assessed using a quantitative reverse transcriptase‐PCR. Cell counting kit‐8 and terminal deoxynucleotidyl transferase dUTP nick end labeling assays and specific kits were employed to assess cell viability, apoptosis, reactive oxygen species (ROS), malondialdehyde, iron, glutathione, and glutathione peroxidase 4 (GPX4) levels.ResultsThe interaction between miR‐1278 and circHIPK3 or DNMT1 was validated via luciferase reporter and RNA pull‐down assays. circHIPK3 expression was found to be high in GDM placental tissues, plasma, and cells, with a high diagnostic value. In high glucose (HG)‐induced HTR‐8/SVneo cells, the inhibition of circHIPK3 provoked cell viability and mitigated cell apoptosis, ROS, and iron levels, but it was rescued through the downregulation of miR‐1278. Mechanism experiments showed that circHIPK3 bound with miR‐1278 targeting DNMT1 in GDM. The elevation in DNMT1 expression abolished the effects of miR‐1278 overexpression on ferroptosis in HG‐cultured HTR‐8/SVneo cells.ConclusionsOverall, circHIPK3 might facilitate ferroptosis via miR‐1278/DNMT1 to regulate GPX4 DNA methylation in HG‐cultured HTR‐8/SVneo cells. CircHIPK3 could be a therapeutic agent for GDM treatment.