BD1-biased BET inhibition attenuates TXNIP-associated inflammation in diabetic MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by metabolic stress, inflammation, and fibrosis, with limited effective therapies. Thioredoxin-interacting protein (TXNIP) links hyperglycemia and oxidative stress to NLRP3 inflammasome activation, but the epigenetic mechanisms sustaining TXNIP induction in diabetic MASH remain unclear. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that promotes inflammatory transcription through chromatin engagement. Here, we examined whether BRD4-associated regulation of TXNIP contributes to diabetic MASH and evaluated LT052, a BD1-biased BET bromodomain inhibitor with preferential BRD4 BD1 activity, in a streptozotocin-accelerated dietary rat model. Diabetic MASH caused severe steatohepatitis, fibrosis, insulin resistance, oxidative stress, NF-κB activation, TXNIP induction, and NLRP3 inflammasome activation. These changes were accompanied by increased BRD4 occupancy at the TXNIP promoter and elevated total hepatic histone H3 acetylation (Ac-H3K9). LT052 markedly improved liver histopathology, metabolic control, redox balance, and inflammatory outcomes, while reducing TXNIP expression, inflammasome activation, and downstream pyroptotic signaling. Mechanistically, LT052 reduced BRD4 occupancy at the TXNIP promoter and decreased total hepatic Ac-H3K9 without altering total BRD4 expression or nuclear BRD4 immunostaining, consistent with reduced BRD4-associated promoter engagement rather than altered BRD4 abundance or localization. Integrated analyses showed broad, dose-dependent improvement across MASH-relevant endpoints. These findings support further investigation of BD1-biased BET inhibition with LT052 as a therapeutic strategy for diabetic MASH.