Lactate promotes premature aging of preeclampsia placentas through histone lactylation-regulated GADD45A

Premature placental aging has been linked to preeclampsia (PE), with lactate identified as a promoter of cellular senescence in various cell types. In this study, we explored the role and underlying mechanisms of lactate in driving premature placental aging associated with PE.

To evaluate senescence markers in placental samples or trophoblast cells, we conducted SA-β-Gal staining, western blotting, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence assays. SiRNA transfection was used to reduce GADD45A expression in HTR-8/SVneo cells exposed to lactate. Additionally, chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to analyze histone lactylation at the GADD45A promoter region.

SA-β-Gal staining indicated a significant increase in senescent cell proportions in placentas from PE patients compared to controls. Treatment with lactate enhanced senescence in trophoblast cells, leading to an increase in P16 expression. RNA sequencing analysis showed that genes differentially expressed in lactate-treated cells were involved in pathways linked to cellular senescence. Additionally, lactate augmented GADD45A expression and increased histone lactylation at its promoter region, while knocking down GADD45A in trophoblast cells mitigated the senescence induced by lactate.

Lactate promotes trophoblast senescence through epigenetic upregulation of GADD45A expression, offering fresh perspectives on the molecular mechanisms and potential treatment targets for PE.