GYS2 links cuproptosis and M1 macrophage polarization in preeclampsia: a functional and mechanistic analysis.

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.