TET3 promotes preeclampsia by regulating PDK4-mediated glucose metabolism reprogramming in trophoblasts.

Extra villous trophoblasts (EVTs) dysfunction impairing spiral artery remodeling (SAR) is a key preeclampsia (PE) factor. ScRNA-seq and bioinformatics analyses of preeclamptic placentas revealed the upregulation of TET3, a newly recognized regulator of epigenetic reprogramming. Untargeted metabolomics further associated TET3 with the trophoblast glucose metabolism. In vitro functional and metabolic assays demonstrated that elevated TET3 levels inhibited EVT proliferation and migration by dysregulating the mitochondrial glucose metabolism. Through integrated ScRNA-seq, microarray analysis, metabolic profiling, and chromatin immunoprecipitation assays, we found that in human trophoblasts, TET3 suppressed the expression of PDK4 by upregulating the transcription factor FOS. Mechanistically, TET3 bound to the FOS promoter and induced DNA demethylation, chromatin remodeling, and transcriptional activation. As a downstream effector, FOS bound directly to the PDK4 promoter and repressed its expression. This regulatory axis was validated in various animal models and in clinical placental specimens. Collectively, our study established that the TET3/FOS/PDK4 pathway is a critical driver of PE pathogenesis, thus offering a novel therapeutic target for PE.