SETD7-mediated epigenetic regulation of LncRNA XIST promotes trophoblast pyroptosis: a study in preeclampsia mouse and cell models

BACKGROUND: Pre-eclampsia (PE) is a severe pregnancy-specific hypertensive disorder that poses significant risks to both maternal and fetal health. This study seeks to elucidate the mechanism by which SETD7 regulates trophoblast cell pyroptosis in PE through epigenetic mechanisms. METHODS: PE mouse model was developed, and cell model was constructed using H/R-treated HTR-8/SVneo cells. SETD7, LncRNA XIST, FOXA1, TMBIM4, GSDMD-N, cleaved Caspase-1, and NLRP3 were detected via qRT-PCR or Western blot. ELISA was employed to measure IL-1β and IL-18. ChIP was employed to assess H3K4me3 and SETD7 enrichments on the promoter of LncRNA XIST. RIP assay was applied to verify interaction of YTHDF2/m6A with FOXA1 mRNA. The stability of FOXA1 mRNA was detected. Dual-luciferase reporter and ChIP were applied to validate the interaction between FOXA1 and TMBIM4. RESULTS: SETD7 exhibited high expression in placental tissues in PE. SETD7 knockdown attenuated IL-1β, IL-18, GSDMD-N, cleaved Caspase-1, and NLRP3 levels. SETD7 suppression ameliorated PE symptoms and inhibited H/R-induced pyroptosis. Mechanistically, SETD7 may upregulate LncRNA XIST expression by increasing H3K4me3 enrichment at the LncRNA XIST promoter. LncRNA XIST recruited YTHDF2 to FOXA1 mRNA, promoted the degradation of FOXA1 mRNA and inhibited FOXA1 expression through m6A modification, thereby reducing TMBIM4 transcription and inducing trophoblast cell pyroptosis via NLRP3 inflammasome activation. CONCLUSION: In the sFlt-1-induced PE mouse model and H/R-treated HTR-8/SVneo cells, SETD7 promotes placental trophoblast cell pyroptosis and exacerbates PE-like symptoms through the LncRNA XIST/FOXA1/TMBIM4 axis.