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Updated: Sep 18, 2026
Network Pharmacology and Validation of the Antidepressant Mechanisms of Qiangzhifang in a Chronic Restraint Stress-induced Depression Rat Model
Published on: June 6, 2025
Naringin alleviates depressive-like behavior in rats by regulating endoplasmic reticulum stress through IRE1/XBP1
Zheng Gong1, Yanni Wang2, Dandan Di3
1Clinical Experimental Center, Northwest University Affiliated Xi'an International Medical Center Hospital, Xi'an, 710100, China; Institute of Maternal and Infant Health, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China.
Abstract:
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.
