NR3C1 and major depressive disorder: Phosphorylation of p38MAPK under stress augments the transcriptional activity of the AP-1 family, influencing the expression of downstream CRH genes and modulating the activity of the HPA axis.[37,38] Additionally, p38MAPK boosts CREB transcription, eliciting inflammatory responses that can harm central neurons, attenuate central reward feedback mechanisms, and dampen positive emotions.[39] Concurrently, proinflammatory factors activate p38MAPK, which hinders GR nuclear translocation and results in abnormal GR phosphorylation, thereby exacerbating the progression of depression.[40]