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GYS2 links cuproptosis and M1 macrophage polarization in preeclampsia: a functional and mechanistic analysis
Huanping Wang1, Haiying Wu1, Li Wang1
1Department of Obstetrics, Henan Provincial People's Hospital, Zhengzhou, 450000, China.
Background:
Preeclampsia (PE) causes high maternal and perinatal morbidity/mortality, with unclear pathogenesis. Given the emerging roles of cuproptosis and M1 macrophage polarization in PE progression, this study investigated the cuproptosis- and M1 macrophage-associated transcriptomic network to identify specific molecular targets underlying trophoblast damage.
Methods:
Placental transcriptomes of controls and severe PE patients were analyzed. Immune infiltration, WGCNA (cuproptosis/M1 macrophage-related modules), DEG screening, and machine learning identified hub genes. Validation was done in GSE148241, H2O2-induced HTR-8/SVneo cells, and PE placental tissues. GYS2/NRIP1 functions were tested via rescue assays; their association was verified by ChIP and dual-luciferase assays.
Results:
Severe PE had increased placental M1 infiltration. WGCNA's blue module correlated with cuproptosis/M1 macrophages, and 5 hub genes were identified, with GYS2 downregulated consistently. GYS2 overexpression attenuated H2O2-induced oxidative stress, cuproptosis, and M1 polarization. NRIP1 inhibited GYS2, and NRIP1 knockdown protected trophoblasts via GYS2 upregulation.
Conclusion:
NRIP1 knockdown-induced GYS2 upregulation alleviates H2O2-induced damage in trophoblasts; GYS2 is a potential PE therapeutic target.