Integrative analysis and experimental validation unveil TNFSF10 as a key PANoptosis inducer driving preeclampsia...

Preeclampsia, a life-threatening pregnancy-specific hypertensive disorder, poses significant risks to maternal and fetal health. Although apoptosis, necroptosis, and pyroptosis have been implicated in its pathogenesis, the involvement of PANoptosis, a newly identified inflammatory cell death pathway integrating these processes, remains unexplored. This study systematically investigated PANoptosis-related mechanisms in preeclampsia and identified potential biomarkers through an integrated approach combining placental transcriptomic analysis, clinical specimen validation, in vivo modeling (preeclampsia serum-induced mouse model), and functional in vitro cell-based experiments. We identified tumor necrosis factor superfamily member 10 (TNFSF10) as a key regulator of PANoptosis activation in preeclamptic placentas. Quantitative analyses revealed significantly elevated expression of canonical PANoptosis markers, cleaved caspase-3, cleaved caspase-7, cleaved caspase-1 and p-MLKL, along with pore formation by GSDME in the cell membrane of preeclampsia placenta. Furthermore, PANoptotic activity in preeclampsia demonstrated a strong correlation with TNFSF10 expression. Functional investigation using the first trimester trophoblast cell line HTR8/SVneo demonstrated that TNFSF10 overexpression induced PANoptosis. In addition, TNFSF10-mediated PANoptosis may facilitate preeclampsia progression by promoting inflammation through NK cell activation and M1 macrophage polarization at the maternal-fetal interface. Our findings not only establish TNFSF10 as a critical mediator of placental PANoptosis, but also reveal its dual role in coordinating trophoblast cell death and immune dysregulation, suggesting novel therapeutic strategies targeting preeclampsia.