Ulcerative colitis (UC) is a chronic inflammatory bowel disease in the colon and rectum. Mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs) have emerged as promising cell-free therapeutics for UC, leveraging their immunomodulatory and tissue-protective properties. However, the specific epigenetic mechanisms by which EVs regulate pyroptosis (an inflammatory cell death pathway) remain poorly understood. This study explores how EVs derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) regulate pyroptosis in colonic epithelial cells of UC by targeting the histone-modifying protein KDM6B, aiming to provide new therapeutic insights for UC. iPSCs were differentiated into MSCs, and their EVs were isolated and characterized. EVs were engineered to carry the circular RNA circ-CCND1 and co-cultured with UC model cells induced by DSS. Cell viability, inflammatory cytokine levels, and key molecular markers related to pyroptosis (NLRP3, cleaved Caspase-1, GSDMD-N) were measured. The molecular mechanism was dissected using RNA-protein binding assays and gene expression analysis, focusing on the circ-CCND1/KDM6B/ELF3/miR-342-3p signaling axis. EV treatment reduced pyroptosis in UC model cells, with enhanced efficacy when EVs carried circ-CCND1. Mechanistically, circ-CCND1 in EVs entered cells and bound to KDM6B, inhibiting its activation of the ELF3 gene, leading to increased miR-342-3p, which in turn suppressed KDM6B expression, forming a feedback loop that dampened pyroptosis. In conclusions, iPSC-MSC-derived EVs inhibit inflammatory cell death in colonic epithelial cells by regulating histone modification-related pathways, highlighting their potential as a novel therapeutic strategy for UC.