Bromodomain-Containing Protein 4 in Ischemia-Reperfusion Injury: Mechanisms, Preclinical Evidence, and Translational...

Ischemia reperfusion (IR) injury is a major contributor to tissue damage and organ dysfunction following ischemic events and clinical interventions such as thrombolysis, revascularization, and transplantation, yet effective pharmacological strategies to limit this injury remain limited. Bromodomain-containing protein 4 (BRD4), an epigenetic reader that recognizes acetylated lysine residues to drive super-enhancer-associated transcription. Upregulated BRD4 has emerged as a key regulator of the inflammatory, endothelial, and cell death pathways underlying post-IR injury pathophysiology. Preclinical evidence across cerebral, cardiac, renal, and hepatic IR injury models indicates that BRD4 hyperactivation amplifies NFκB-dependent inflammatory signaling, while its pharmacological or genetic inhibition confers substantial tissue protection. This review synthesizes current mechanistic understanding of BRD4 in IR injury pathogenesis, evaluates emerging BET/BRD4-targeted therapeutic strategies, and outlines key translational challenges for advancing epigenetic pharmacology toward clinical application in IR-associated disorders.