Naringin alleviates depressive-like behavior in rats by regulating endoplasmic reticulum stress through IRE1/XBP1 pathway.

Prenatal stress (PS) is a recognized risk factor contributing to the development of depressive-like behaviors in offspring. Naringin (NRG), a bioactive flavonoid abundant in citrus fruits, exhibits notable antidepressant and neuroprotective properties. This study aimed to elucidate the molecular mechanisms underlying NRG's effects in PS offspring, focusing on IRE1/XBP1 pathway of endoplasmic reticulum stress (ERS). The results demonstrated that NRG treatment significantly alleviated depressive-like behavior and attenuated hippocampal neuronal damage in PS offspring rats. Integrative network pharmacology and molecular docking analyses predicted that NRG may interact with ERS-related proteins (GRP78, CHOP, IRE1, XBP1). Consistently, PS exposure elevated the expression of GRP78, CHOP, p-IRE1, XBP1s, Bax, and Caspase-12 while decreasing Bcl-2, triggering ERS-mediated neuronal apoptosis. NRG treatment effectively reversed these molecular alterations and suppressed apoptosis. Strong correlations were observed between behavioral improvements and the downregulation of IRE1/XBP1 pathway components and apoptotic markers. In conclusion, NRG exerts antidepressant-like effects in PS-exposed offspring likely by suppressing hippocampal ERS via the IRE1/XBP1 pathway, thereby reducing neuronal apoptosis. These findings position NRG as a promising candidate for novel antidepressant therapeutics.