Hippocampal Glucuronyl C5-epimerase promotes stress resilience by directly engaging PI3K through a non-enzymatic mechanism

Major depressive disorder (MDD) seriously affects human physical and mental health and causes global socioeconomic burdens. Stress-induced depressive etiology is linked to dendritic atrophy in the hippocampus, however, the underlying mechanism was poorly understood. Here, we identify that glucuronyl C5-epimerase ( Glce ), a heparan sulfae-modifying enzyme, as a critical regulator of hippocampal dendritic integrity and stress resilience. Genetic ablation of Glce in the hippocampal excitatory neurons is sufficient to induce dendritic atrophy and depressive-like behaviors, whereas its restoration rescues these deficits. Notably, Glce levels are reduced in the plasma of depressed individuals. We further find that Glce functions independently of its enzymatic activity, instead binding directly to and activating PI3K (p85α/p110α), thereby triggering an Akt/CREB/BDNF signaling cascade. Together, our findings uncover a non-canonical role for Glce and establish that Glce –PI3K–BDNF axis is essential for maintaining hippocampal structure and behavioral resilience, thereby highlighting a critical role of Glce in the pathophysiology of depression.