Further, compounds 1, 2, and 3 showed more significant reduction in APAP-induced necrotic area compared to treatment with I-BET151, where all compounds tested moderately reduced neutrophil infiltration. These data highlight that liver damage and necrosis may only be partially BRD4-driven for APAP-and LPSinduced inflammation. Given the clinical risks of pan-BET inhibitors, mainly thrombocytopenia and gastrointestinal bleeding, we sought to investigate our differentially selective inhibitors in this regard. We found that compounds 1, 2, I-BET151, and iBETBD2 were less toxic in a colony-forming megakaryocyte assay compared to compound 3. While the results of I-BET151 cannot yet be explained, the data for 3 suggest pan-D1 inhibitors are more prone to thrombocytopenia risks. However, all compounds showed significant goblet cell reduction as a surrogate for intestinal toxicity. Together, these data support that antiinflammatory activity is possible through a BRD4-dependent mechanism with improved thrombocytopenia risks, though these compounds did not show significant improvement in goblet cell toxicity.