Bone marrow mesenchymal stem cell-derived exosomes exert therapeutic effects on inflammatory bowel disease through miR-148a-3p/Ets-1-dependent inhibition of pyroptosis.

Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory condition of the gastrointestinal tract, characterized by damage to intestinal epithelial cells (IECs) and inflammation. Mesenchymal stem cell-derived exosomes show therapeutic potential in IBD, but the underlying mechanisms remain unclear. This study investigates the therapeutic potential of bone marrow mesenchymal stem cell (BMSC)-derived exosomes and their molecular mechanism in IBD. We isolated and characterized exosomes from mouse BMSCs, confirming their typical size, morphology, and marker expression. In a dextran sulfate sodium (DSS)-induced mouse IBD model, administration of BMSC-derived exosomes alleviated disease severity, colon shortening, and histopathological damage. In LPS + ATP-stimulated IECs, BMSC-exos upregulated miR-148a-3p expression, enhanced cell viability, and suppressed pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), ASC, cleaved caspase-1, and the N-terminus of GSDMD (GSDMD-N), and inflammatory cytokines interleukin 1β (IL-1β), IL-18, tumor necrosis factor-α (TNF-α), and IL-6. Bioinformatics and dual-luciferase reporter assays identified E26 avian leukemia oncogene 1, 5' domain (Ets-1) as a direct target of miR-148a-3p. Ets-1 knockdown reversed the effects of miR-148a-3p inhibition on IEC pyroptosis and inflammation. In conclusion, BMSC-derived exosomes deliver miR-148a-3p to IECs, where it targets Ets-1 to suppress cellular pyroptosis and inflammatory responses, offering a novel therapeutic strategy for IBD.