Background <p>Preeclampsia (PE) is a severe gestational disorder associated with impaired placental function. Necroptosis contributes substantially to trophoblast injury in PE, though the upstream epigenetic regulatory pathways are not yet fully elucidated. This study investigated how the deubiquitinase USP22 suppresses trophoblast necroptosis via epigenetic modulation of the KAT2A-SFRP1 axis.</p> Methods <p>Preeclamptic and normal placental tissues were analyzed for USP22 and necroptosis pathway components by immunohistochemistry. Hypoxic conditions established in HTR-8/SVneo trophoblasts simulated the preeclamptic microenvironment. Cell death modality was characterized through complementary approaches including flow cytometry, cell viability assays, and transmission electron microscopy. Pathway selectivity was determined through systematic pharmacological inhibition of necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagy. RNA sequencing identified genome-wide transcriptional responses to USP22 perturbation. Direct protein-protein interactions and locus-specific histone modifications at the SFRP1 promoter were resolved by co-immunoprecipitation and chromatin immunoprecipitation followed by quantitative PCR. USP22-mediated deubiquitination of KAT2A and substrate ubiquitin chain linkage specificity were elucidated using protein stability assays, ubiquitination analysis, and catalytic activity-dependent rescue with a C185A point mutant. Findings were further validated in an in vivo L-NAME-induced rat model of PE.</p> Results <p>USP22 was significantly downregulated in PE placental tissues, concomitant with elevated expression of RIPK1, RIPK3, and MLKL. Necroptosis was confirmed as the dominant death modality in hypoxic trophoblasts. USP22 knockdown exacerbated necroptotic signaling, while USP22 overexpression restored H3K9ac and H3K27ac levels and suppressed necroptosis. RNA sequencing analysis identified 1,186 differentially expressed genes following USP22 knockdown, including notably repressed expression of the Wnt antagonist SFRP1. Mechanistically, USP22 directly interacted with KAT2A and stabilized it by selectively cleaving K48-linked polyubiquitin chains. This stabilization sustained KAT2A-dependent histone acetylation at the SFRP1 promoter, thereby maintaining SFRP1 transcription. Importantly, SFRP1 restoration in USP22-deficient trophoblasts substantially mitigated cell death and decreased the p-MLKL/MLKL ratio. The L-NAME rat PE model further confirmed coordinated downregulation of USP22, KAT2A, SFRP1, and histone acetylation marks in vivo.</p> Conclusion <p>USP22 maintains trophoblast survival through selective K48-deubiquitination of KAT2A, which stabilizes KAT2A and sustains histone acetylation at the SFRP1 promoter, thereby promoting SFRP1 transcription and suppressing RIPK1-RIPK3-MLKL-mediated necroptosis. The USP22-KAT2A-SFRP1 axis represents a novel epigenetic checkpoint in PE pathogenesis and a potential therapeutic target for placental insufficiency.</p>