Dihydromyricetin ameliorates lipopolysaccharide‒induced hepatic injury in chickens by activating the Nrf2/Keap1 pathway and regulating mitochondrial dynamics

Dihydromyricetin (DHM) is a flavonoid found in vine tea that exhibits various pharmacological characteristics, including antibacterial, antiapoptotic, and antioxidant effects. Our previous study revealed that DHM can alleviate chicken hepatic injury, but the underlying mechanism has not been elucidated. To further investigate the protective mechanism of DHM, this study firstly predicted by network pharmacology that the potential regulatory pathways of DHM on hepatic injury. Subsequently, the experimental models were replicated in vivo and in vitro using Hy‒Line white broiler chickens and chicken primary hepatocytes treated with DHM and with/ without LPS. Network pharmacology results showed that the effect of DHM on hepatic injury might be related to oxidative stress and mitochondrial function. Further experiments showed that DHM significantly reduced LPS‒elicited serum ALT and AST activities, promoted antioxidant enzyme activities and scavenged ROS in chicken liver or primary hepatocytes. Molecular docking studies showed that DHM could directly bind to Nrf2 and Keap1. Furthermore, DHM treatment regulated the expression of Nrf2 and Keap1, thereby upregulating the downstream expression of antioxidant factors, including HO‒1 and NQO1, in vivo and in vitro. Moreover, DHM modulated the expression of mitochondrial dynamics related factors, including Mfn1/2, Opa1, Drp1, and Fis1, meanwhile, DHM ameliorated mitochondrial structural damage and increased the MMP. Overall, these results suggested that DHM activated the Nrf2/Keap1 pathway and regulated the balance between mitochondrial fusion and fission, ultimately alleviating chicken hepatic injury induced by LPS.