USP22 Suppresses Trophoblast Cell Necroptosis in Preeclampsia by Stabilizing KAT2A-Mediated Histone Acetylation at the SFRP1 Promoter

This study investigates the role of USP22 in trophoblast necroptosis and preeclampsia (PE). USP22 expression was significantly downregulated in PE placental tissues, accompanied by elevated necroptosis markers RIPK1, RIPK3, and MLKL. A hypoxic HTR-8/SVneo trophoblast cell model recapitulated the PE microenvironment, where necroptosis was confirmed as the dominant death modality. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA-seq identified 1,186 differentially expressed genes upon USP22 knockdown, including marked repression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it via selective removal of K48-linked polyubiquitin chains, sustaining KAT2A-dependent histone acetylation at the SFRP1 promoter to maintain SFRP1 transcription. SFRP1 restoration in USP22-deficient trophoblasts reduced cell death and decreased p-MLKL/MLKL ratio. The L-NAME rat PE model confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation in vivo.