NDRG2 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 effective rescue of depressive-like phenotypes. These findings reveal a key mechanism of astrocyte death in depression, wherein NDRG2 functions as an adaptor to promote PP2A-mediated AKT dephosphorylation, thereby initiating the pro-apoptotic signaling pathway, and disclose a druggable pathway for developing antidepressants targeting astrocyte preservation.