Background <p>Preeclampsia (PE) is a pregnancy-specific disorder posing significant maternal-fetal risks, while interferon regulatory factor 1 (IRF1) is a transcriptional regulator associated with inflammatory responses. In this study, we aim to explore the pivotal correlation between PANoptosis and PE pathogenesis, as well as the regulatory role of IRF1 in PE progression.</p> Methods <p>Bioinformatics analysis identified differential transcription factors (TFs) and their association with PANoptosis in PE. In vitro, hypoxic HTR-8/SVneo cells were used; dual-luciferase reporter assay verified TFs’ binding to the HDAC1 promoter, and IRF1-knockdown HTR-8/SVneo cells were established. CCK-8, colony formation, flow cytometry, wound healing, and transwell assays assessed cell viability, proliferation, apoptosis, migration, and invasion; angiogenesis assay evaluated vascular remodeling, and western blot detected PANoptosis-related protein expression. In vivo, a PE rat model was established with L-NAME; placental tissues were collected, and histopathological changes were analyzed via HE staining and immunohistochemistry.</p> Results <p>IRF1 was identified as a key PANoptosis-related TF at the intersection of 203 differential TFs and 65 PANoptosis-related genes, regulating HDAC1 by binding to its upstream regulatory region. Based on this, knockdown of IRF1 in HTR-8/SVneo cells increased HDAC1 expression, repaired cell viability, proliferation, migration, invasion, angiogenesis, and decreased the expression of PANoptosis markers (GSDMD, Caspase1/3/8, p-MLKL, p-RIPK3). In PE rats, sh-IRF1 alleviated hypertension, proteinuria, and fetal growth restriction, while placental HDAC1 upregulation mitigated trophoblast dysfunction and inhibited PE progression.</p> Conclusion <p>Transcription factor IRF1 modulates HDAC1 and PANoptosis-associated signaling to regulate PE progression, offering new insights for PE prevention and management.</p> Clinical trial number <p>Not applicable.</p>