Synaptojanin-2-binding protein ameliorates oxidative stress, neuroinflammation and depression-like behaviors via SYNJ2/PIP₂/IP₃ signaling pathway

Depression is a neuro-psychiatric disorder that seriously impairs human physical and mental health. Its clinical treatment effect is not satisfactory and the pathogenesis is unclear. Therefore, it is urgent to clarify its pathological mechanism to provide a new direction for the treatment of depression. The "pathological triad", comprising oxidative stress (an imbalance between reactive oxygen species and antioxidant defenses), neuroinflammation (inflammatory responses within the central nervous system), and apoptosis (programmed cell death), has emerged as a central mechanistic driver underlying the pathophysiology of depression. The present study found that chronic unpredictable mild stress (CUMS) drives a significant down-regulation of the synaptojanin-2-binding protein (SYNJ2BP) expression in hippocampal CA1 subregion. Overexpression of SYNJ2BP mitigates oxidative stress, neuroinflammation, neuronal apoptosis and synaptic structural impairment, while concurrently ameliorating depressive- and anxiety-like phenotypes by interacting with SYNJ2 to modulate phosphatidylinositol 4,5-bisphosphate (PIP₂)/inositol 1,4,5-trisphosphate (IP₃) metabolism, and subsequently suppress downstream p38/JNK signaling cascades. Conversely, SYNJ2BP knockdown or exogenous PIP₂ administration abrogates these protective effects, whereas inhibition of IP₃ signaling recapitulates the beneficial outcomes of SYNJ2BP overexpression. Collectively, our findings reveal a new SYNJ2BP/SYNJ2/PIP₂/IP₃ signaling axis in neurons of hippocampal CA1 subregion that critically mediates CUMS-induced neuronal damage and emotional behavioral deficits, thereby potentially providing therapeutic targets for depression treatment.