To investigate the protective role of MG53 in colitis and elucidate its mechanisms in regulating NLRP3 inflammasome activation in IBD.<h4>Methods</h4>We used dextran sodium sulfate (DSS)-induced colitis models comparing <i>MG53</i> knockout (<i>MG53</i> <sup>-/-</sup>) and wild-type (WT) mice, assessing disease severity, MG53 tissue uptake, and therapeutic effects of recombinant human MG53 (rhMG53). Here, NLRP3 is linked to inflammatory bowel disease.