Brucea javanica oil emulsion ameliorates ulcerative colitis by upregulating Deoxyribonuclease 2 to suppress cytosolic DNA-sensing signaling.

BJOE treatment alleviated DSS-induced colitis and reduced intestinal permeability in mice.

• UC was induced in mice using dextran sulfate sodium (DSS) and treated with oral BJOE.
• Disease severity, histopathology, and intestinal permeability (FITC-dextran) were assessed as outcome measures.
• BJOE preserved epithelial junction proteins and ultrastructure in DSS-treated mice.
• Serum biochemistry and junctional protein expression were used to confirm protective effects.

BJOE partially remodeled DSS-associated gut microbiota dysbiosis.

• Gut microbiota were analyzed by 16S rRNA sequencing.
• BJOE treatment was associated with suppression of Firmicutes expansion.
• Shifts in key genera were observed following BJOE treatment.
• The remodeling was described as partial, not complete restoration of microbiota composition.

Multi-omics analyses converged on cytosolic DNA sensing and identified DNase2 as a key molecular node in colitis.

• LC-MS profiling was integrated with clinical transcriptomic co-expression analysis, network pharmacology, and colon proteomics.
• DNase2 (deoxyribonuclease 2) was highlighted as a key node by these converging analyses.
• Cytosolic double-stranded DNA accumulation was observed in colitis conditions.
• The cGAS-STING pathway was identified as activated downstream of DNase2 reduction in colitis.

DNase2 expression was reduced in colitis and was restored by BJOE treatment.

• DNase2 reduction in colitis was accompanied by cytosolic double-stranded DNA accumulation.
• Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway was observed concurrent with DNase2 reduction.
• BJOE treatment restored DNase2 levels and attenuated cGAS-STING pathway activation.
• Mechanistic validation was performed in DSS-injured NCM460 epithelial cells using Western blotting, RT-qPCR, and immunofluorescence.

DNase2 knockdown abolished the protective effects of BJOE in epithelial cells.

• DNase2 silencing experiments were conducted in NCM460 epithelial cells.
• DNase2 knockdown abolished the DNase2-dependent effects of BJOE, confirming the mechanistic dependence on this target.
• This finding established that BJOE's effects on cytosolic DNA sensing are mediated specifically through DNase2.
• Cellular thermal shift assay and molecular docking were used to further validate BJOE interaction with DNase2.

BJOE is a clinically approved phytomedicine with anti-inflammatory effects whose mechanism in ulcerative colitis was previously undefined.

• BJOE is described as a clinically approved phytomedicine with reported anti-inflammatory effects.
• Its molecular mechanism and therapeutic potential in UC were not defined prior to this study.
• The study aimed to provide a rationale for repurposing BJOE in UC.
• The study focused specifically on epithelial cytosolic DNA sensing as a mechanistic target.