AT1, a small molecular degrader of BRD4 based on proteolysis targeting chimera technology alleviates renal fibrosis and inflammation in diabetic nephropathy.

Both type 1 and type 2 diabetes can lead to diabetic nephropathy (DN), a serious microvascular complication. Bromodomain 4 (BRD4), a member of the BET protein family, has been linked to various diseases, including cancer, inflammation, and fibrosis, and may be involved in the development of diabetes and its complications. In this study, we first explored the role and mechanism of BRD4 in DN. We found that BRD4 expression was upregulated in both diabetic cells and animal models, and that BRD4 knockdown alleviated DN. Therefore, we next investigated the effect of AT1, a small-molecule degrader of BRD4 based on proteolysis targeting chimera (PROTAC) technology, on DN improvement. PROTAC has seldom been applied to non-oncological diseases, and this study represents the first application of AT1 to DN. Finally, we explored the molecular mechanisms underlying DN improvement.