Mangiferin Protects DNase 2 Abundance via Nrf2 Activation to Prevent Cytosolic mtDNA Accumulation during Liver Injury

Abstract

ScopeMitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage‐associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aims to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on deoxyribonuclease 2 (DNase 2) protection from oxidative damage.Methods and resultsMangiferin administration effectively protects against hepatotoxicity in mice subjected to CCl4 challenge or bile duct ligation (BDL) surgery. Moreover, mangiferin activates nuclear factor erythroid 2‐related factor (Nrf2)‐antioxidant signaling, reduces cytosolic mtDNA accumulation, and suppresses Toll‐like receptor 9 (TLR‐9)/myeloid differentiation factor 88 (MyD88)‐dependent inflammation in the liver. The study prepares hepatic mtDNA to stimulate hepatocytes, and finds that mangiferin protects DNase 2 protein abundance. mtDNA induces reactive oxygen species (ROS) production to promote DNase 2 protein degradation through oxidative modification, but mangiferin protects DNase 2 protein stability in a Nrf2‐dependent manner. In hepatic Nrf2 deficiency mice, the study further confirms that Nrf2 induction is required for mangiferin to clear cytosolic mtDNA and block mtDNA‐mediated TLR9/MyD88/nuclear factor kappa‐B (NF‐κB) inflammatory signaling cascades.ConclusionThese findings provide new insights into the role of mangiferin as a liver protecting agent, and suggest protection of DNase 2 as a novel therapeutic strategy for pharmacological intervention to prevent liver damage.