In this study, we used the chronic restraint stress-induced model of depression as well as cultured HAPI cells treated with dexamethasone (DEX, a glucocorticoids hormone) to investigate whether chronic stress-induced hippocampal neuroinflammation is mediated by the GR-NF-κB-NLRP3 pathway, and which might be a new target and offer new perspectives on depression research. Here, NFKB1 is linked to major depressive disorder.