biostudies-literatureWang ZNational Natural Science Foundation of China (National Science Foundation of China)1585https://www.ebi.ac.uk/biostudies/studies/S-EPMC12623748biostudies-literatureUnknown8(1)The loss of astrocytes represents a key pathological hallmark of major depressive disorder, yet its mechanisms remain elusive. Here, we identified NDRG2 as a critical regulator of astrocyte apoptosis in depression. NDRG2 expression is upregulated in depression models, concomitant with astrocyte loss. Overexpression of NDRG2 in astrocytes triggered apoptosis and depressive-like behaviors, with inhibition of AKT and activation of FoxO3a-Puma apoptotic signaling pathway. Mechanistically, NDRG2 recruits PP2A to AKT, facilitating its dephosphorylation and subsequent inactivation, then promotes the nuclear translocation of FoxO3a, leading to the transcriptional activation of the pro-apoptotic factor Puma. Crucially, NDRG2 knockdown in astrocytes effectively prevented astrocytic apoptosis, with eCommunications biologyNDRG2 upregulation induces astrocytic apoptosis via AKT inhibition and FoxO3a-Puma activation in depression.PMC126237488217142632300792Yang JZhang HQin XLiu RZhang LLiu YLai YYang WZhang YZeng JKang MWang XWang ZKe DfalseNDRG2 upregulation induces astrocytic apoptosis via AKT inhibition and FoxO3a-Puma activation in depression.The loss of astrocytes represents a key pathological hallmark of major depressive disorder, yet its mechanisms remain elusive. Here, we identified NDRG2 as a critical regulator of astrocyte apoptosis in depression. NDRG2 expression is upregulated in depression models, concomitant with astrocyte loss. Overexpression of NDRG2 in astrocytes triggered apoptosis and depressive-like behaviors, with inhibition of AKT and activation of FoxO3a-Puma apoptotic signaling pathway. Mechanistically, NDRG2 recruits PP2A to AKT, facilitating its dephosphorylation and subsequent inactivation, then promotes the nuclear translocation of FoxO3a, leading to the transcriptional activation of the pro-apoptotic factor Puma. Crucially, NDRG2 knockdown in astrocytes effectively prevented astrocytic apoptosis, with e2025-01-01T00:00:00Z2025 Nov2026-06-05T16:35:30.607Z2026-05-18T03:13:11.277ZS-EPMC126237484124943910.1038/s42003-025-08968-y