Hesperidin may improve depressive symptoms by binding NLRP3 and influencing the pyroptosis pathway in a rat model.

Objective: Major depressive disorder (MDD) is a debilitating psychiatric disorder which is common and endangers human physical and mental health. Studies have shown that hesperidin could improve the symptoms of depression with unclear mechanisms.

Method: In this study, hesperidin was administered to chronic unpredictable mild stress (CUMS) depressed mice before behavioral test, network pharmacology analysis, RNA expression microarray analysis, pathway validation and molecular docking experiments.

Results: we found that hesperidin intervention could significantly improve the depressive symptoms and downregulate the expression level of pyroptosis pathway including caspase 1 (Casp1), interleukin 18 (IL18), interleukin-1β (IL-1β) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In addition, we found that hesperidin could possibly bind to NLRP3.

Conclusions: Our study demonstrated that hesperidin had huge potential as anti-depressive neuroprotectant, and may play a role in treating MDD by regulating NLRP3-mediated pyroptosis.