Lumican deficiency dysregulates trophoblast function via PI3K/AKT and P53 signaling in preeclampsia.

Lumican, an extracellular matrix (ECM) component highly expressed in placenta, is implicated in preeclampsia (PE) pathogenesis, though its precise mechanisms in trophoblast function and PE development remain unclear. Transcriptomic analysis of a PE rat model induced by L-NAME revealed altered placental gene expression. Lumican expression progressively increased throughout rat and human gestation but was significantly downregulated in PE patient and model placentas. Functional assays showed shRNA-mediated lumican knockdown inhibited trophoblast proliferation, migration, and invasion while promoting apoptosis. This knockdown also influenced the phosphorylation of key proteins within the PI3K/AKT and P53 signaling pathways. Co-treatment with the PI3K agonist 740 Y-P activated this pathway, enhancing trophoblast proliferation and invasion, effects antagonized by lumican knockdown. In vivo, adenovirus-mediated lumican shRNA induced PE-like phenotypes: elevated systolic blood pressure, increased 24 h urinary protein, higher plasma sFlt-1 levels and sFlt-1/PlGF ratio. Histopathological analyses demonstrated abnormal placental villi development and renal glomerular endothelial damage. Immunohistochemistry confirmed lumican deficiency reduced PI3K, AKT, and MDM2 while upregulating P53 in placental tissues. Collectively, our findings demonstrate that reduced lumican expression contributes to PE by impairing trophoblast function via disruption of the PI3K/AKT and P53 signaling pathway, thus providing a mechanistic basis for its further exploration as a diagnostic marker and therapeutic target.