To help address mechanistic questions surrounding BET bromodomain dependence, domainselective pan-D1 and pan-D2 BET inhibitors have been developed. Our work and the Zhou lab have developed BRD4-selective bromodomain inhibitors including UMN627, Compound 30, 34 iBRD4(D1), ZL0590, and ZL0494 which inhibit BRD4-D1 (Figure ). Using UMN627 and Compound 30, we showed that BRD4-D1 inhibition alone was a viable method to reduce NF-κB-mediated inflammatory signaling in cellular and mouse models of liver fibrosis and alcoholic hepatitis. However, these compounds suffer from off-target general cytotoxicity at micromolar concentrations, limiting their further use. Our work also resulted in a triazole-based inhibitor with a different selectivity profile that was biased towards BET D1s, DW34, which was better tolerated, but its anti-inflammatory activity has yet to be reported. Sterile inflammation is a key pathophysiological process in two highly prevalent chronic liver diseases, metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-associated liver disease (ALD). While BET proteins are gaining interest as targets for MASH and ALD, we focus here on ALD given the lack of regulatory agency-approved therapies, undersized pipeline compared to MASH, and our discovery of a super-enhancer which drives inflammation in ALD. We recently reported that CXCL expression by liver sinusoidal endothelial cells (LSECs), mediated through a BRD4/NF-κB-dependent mechanism, drives liver inflammation in a mouse model of ALD. There are also similar reports of BRD2dependent mechanisms. Here, we evaluate the role of inhibitors of the BET proteins with a diverse selectivity profile in the context of liver inflammation based on LPS-and drug-induced liver toxicity. Using a suite of BRD4-and domain-selective inhibitors, we now assess the effects of these differentially selective BET inhibitors in transformed LSECs on chemokine expression and investigate general toxicity to establish a therapeutic window. For use as in vivo probes, we also characterize the liver microsome stability, in vivo pharmacokinetics (PK), and tissue distribution of three differentially-selective inhibitors that are either BRD4-D1 selective or are pan-D1 biased. We compare these inhibitors to pan-BET inhibitor, I-BET151, and pan-D2 inhibitor, iBETBD2, in two representative mouse models of liver inflammation that recapitulate key inflammatory pathways activated in ALD. We characterize the effects of these inhibitors on chemokine expression, cellular necrosis, and neutrophil recruitment. These results demonstrate that pan-D1 biased inhibitors are more efficacious than pan-D2 inhibitors under these conditions. However, subsequent toxicity experiments demonstrate pan-D1 biased inhibitors have a significant toxicity toward goblet cells and megakaryocytes, indicating that these compounds may cause GI symptoms and thrombocytopenia similarly to previously characterized pan-BET inhibitors. Encouragingly, our preliminary analysis suggests BRD4-D1 inhibitors may be better tolerated for reducing the clinical observations of thrombocytopenia induced by pan-BET inhibitors, although goblet cell toxicity may be a BRD4-driven effect.