Bromodomain protein 4 inhibitor JQ-1 alleviates hepatic ischemia-reperfusion injury by blocking the NLRP3/caspase-1 pathway.

BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury is a major challenge in liver surgery and transplantation. Bromodomain protein 4 (BRD4) has emerged as a promising target due to its role in oxidative stress and inflammation. JQ-1, a specific BRD4 inhibitor, has shown protective effects on organs suffering I/R injury. This study aims to investigate the expression of BRD4 in liver tissues after I/R injury and to explore its role in this process using JQ-1 both in vivo and in vitro. METHODS: Our study established a mouse model of hepatic I/R injury and investigated the protective effect of JQ-1. We compared the histological features, BRD4 expression, and liver enzyme levels between JQ-1-treated and untreated groups. Additionally, the antioxidant properties of JQ-1 were analyzed in RAW 264.7 cells by evaluating cytokine expression, NLRP3 inflammasome activity, and reactive oxygen species production. RESULTS: BRD4 was abundantly expressed in liver tissues after hepatic I/R injury, while JQ-1 treatment had antioxidant and hepatoprotective effects. JQ-1 also suppressed pro-inflammatory cytokine release in vitro. Furthermore, we clarified the mechanism by which JQ-1 enhances liver injury recovery through Kupffer cells by blocking the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3)/caspase-1 pathway. CONCLUSION: JQ-1 has potential as a pre-clinical emergency therapy for hepatic I/R injury. Its ability to inhibit BRD4 and modulate the inflammatory response in Kupffer cells offers a promising avenue for future clinical intervention.