Hesperidin mitigates copper nanoparticle exposure-induced mitochondrial unfolded protein response through the SIRT3-FOXO3A signaling pathway

Background: With the increasing application of copper nanoparticles (CuNPs) across various fields, its toxicity and hazards are gradually being confirmed. Hesperidin (Hes), a flavonoid compound with extensive antioxidant and anti-inflammatory effects, has recently attracted public attention.

Methods: Molecular docking was employed to investigate the potential binding sites between Hes and SIRT3. The activation of the SIRT3-FOXO3A signaling pathway by Hes was further validated through a series of experiments in vitro and vivo.

Results: The results indicate that exposure to CuNPs can cause pathological damage to liver. Compared with the control group, exposure to CuNPs induced the accumulation of Reactive Oxygen Species and mitochondrial UPR^mt in broiler liver, specifically manifested as an increase in Reactive Oxygen Species and the gene and protein levels of UPR^mt related proteins. The molecular docking results indicate that Hes and SIRT3 have potential binding sites. However, after treatment with Hes, pathological damage in liver was alleviated. At the same time, we found that the SIRT3-FOXO3A signaling pathway was activated, leading to a significant decrease in the expression levels of proteins and genes related to UPR^mt.

Conclusion: Hes can ameliorate hepatic oxidative damage and UPR^mt induced by exposure to CuNPs by activating the SIRT3-FOXO3A pathway.

Copper nanoparticles; FOXO3A; Hesperidin; Liver; Mitochondrial unfolded protein response; SIRT3.