OBJECTIVE: This study aimed to elucidate the role of BAP1 in inflammatory bowel disease (IBD) and elucidate the underlying mechanism. METHODS: A colitis model was established in C57BL/6 mice with dextran sulfate sodium (DSS) and in the HT-29 cell line. Ferroptosis-related gene expression was analyzed via RNA sequencing, qRT-PCR, and Western blotting. Ferroptosis was induced by Fin56, and oxidative stress markers, iron levels, and cystine uptake were assessed. BAP1 knockdown and overexpression experiments were conducted in vivo and in vitro to determine its impact on SLC7A11 expression, ferroptosis, and intestinal inflammation. RESULTS: BAP1 was significantly upregulated in DSS-induced colitis and correlated with increased ferroptosis markers. Knockdown of BAP1 alleviated colitis symptoms, reduced inflammatory cytokine levels, and decreased bacterial translocation. In vitro, BAP1 promoted ferroptosis by increasing oxidative stress and iron accumulation while inhibiting SLC7A11 expression. The C91A mutation of BAP1 failed to suppress SLC7A11, suggesting that BAP1-mediated ferroptosis is dependent on its deubiquitinase activity. Furthermore, BAP1 overexpression inhibited cystine uptake by repressing SLC7A11, whereas SLC7A11 overexpression rescued cystine uptake and mitigated ferroptosis. CONCLUSION: Our findings reveal that BAP1 exacerbates IBD by promoting ferroptosis through the inhibition of SLC7A11. Knockdown of BAP1 alleviates colitis by suppressing ferroptosis, highlighting a potential therapeutic strategy for IBD. Targeting the BAP1-SLC7A11 axis may provide novel insights into the treatment of ferroptosis-related intestinal diseases.