TRP/p53 protects adult hippocampal neural stem cells from psychological stress by preventing autophagic cell death

in neural stem cells heightened vulnerability to chronic restraint stress (CRS), resulting in worsened memory deficits and mood disturbances compared to wild-type controls. Mechanistically, CORT facilitated MAP1LC3/LC3-mediated autophagic degradation of TRP53 through its LC3-interacting region (LIR), thereby promoting ACD. However, overexpression of either wild-type TRP53 or a degradation-resistant LIR mutant suppressed ACD by interfering with the ATG14-containing PIK3C3/VPS34 complex. Moreover, treatment with RITA, a small-molecule activator of TRP53, disrupted the TRP53-LC3 interaction, stabilized TRP53 levels, and protected ahNSCs from ACD, ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify TRP53 as a key negative regulator of ACD in ahNSCs and suggest that TRP53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN.