Systematic profiling reveals hepatic immune and metabolic dysregulation in DNASE1L3-deficient mice

Deoxyribonuclease 1-like 3 (DNASE1L3) is a secreted endonuclease essential for degrading extracellular DNA and maintaining immune tolerance, but its role in hepatic immune-metabolic regulation remains unclear. Using multi-omics analyses combined with immunophenotyping, we demonstrate that <i>Dnase1l3</i>-deficient (knockout, KO) mice exhibit disrupted myeloid differentiation, Kupffer cell M1 polarization (M1), and progressive hepatic steatosis. Integrated transcriptomic, proteomic, and metabolomic profiling revealed activation of damage-associated molecular pattern (DAMP) sensing, endoplasmic reticulum stress, redox imbalance, ferroptosis susceptibility, and lipid metabolic reprogramming. Whole-genome resequencing further identified chromosome 4 mutation hotspots linked to iron metabolism, oxidative stress, and inflammation. These findings establish DNASE1L3 as a key regulator of hepatic immune-metabolic homeostasis and suggest that its deficiency drives a pathological cascade involving pattern recognition receptor activation, endoplasmic reticulum stress, and ferroptosis, ultimately leading to non-alcoholic fatty liver disease (NAFLD). This study provides a mechanistic framework for nucleic acid-driven immunometabolic dysregulation in chronic liver disease.