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

Scope Mitochondrial 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 results Mangiferin administration effectively protects against hepatotoxicity in mice subjected to CCl 4 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. Conclusion These 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.