NMDARs activation regulates endothelial ferroptosis via the PP2A-AMPK-HMGB1 axis

This study investigated the role of N-methyl-D-aspartate receptor (NMDAR) activation in inducing ferroptosis in vascular endothelial cells (VECs) both in vivo and in vitro. Experiments using NMDA or L-glutamic acid (GLU) showed increased ferroptosis, iron content, MDA, and PTGS2 expression, while decreasing GPX4 expression and GSH concentration in HUVECs. This effect was reversed by ferroptosis inhibitors. RNA sequencing revealed ferroptosis and SLC7A11 involvement. The PP2A-AMPK-HMGB1 pathway was identified as a key regulator of NMDAR activation-induced ferroptosis, confirmed using inhibitors and siRNA. In vivo studies corroborated these findings, demonstrating that NMDA- or GLU-induced ferroptosis was reversed by inhibitors targeting this pathway. The study concludes that NMDAR activation contributes to endothelial cell injury by regulating ferroptosis via the PP2A-AMPK-HMGB1 pathway.

Wei-Min Han, Yi-Xiang Hong, Guo-Sheng Xiao, Rui-Ying Wang, Gang Li