BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation.

Sepsis-associated acute kidney injury (S-AKI) is characterized by complex pathological mechanisms, primarily driven by oxidative stress and inflammation, with NADPH oxidase 4 (NOX4) playing a critical role. However, the regulatory mechanisms underlying NOX4 activation remain incompletely understood. In this study, we found that circulating levels of NOX4 and the chromatin acetylation "reader" bromodomain-containing protein 4 (BRD4) were significantly elevated in S-AKI patients and positively correlated with renal dysfunction markers. These clinical findings were further validated in both LPS-induced and cecal ligation and puncture (CLP)-induced S-AKI models, in which BRD4 and NOX4 were markedly upregulated in the kidney. Prominent induction was observed in renal tubular epithelial cells, and this upregulation was associated with exacerbated inflammation, oxidative stress, and renal injury. Pharmacological inhibition of NOX4 effectively mitigated these pathological changes in both models. Similarly, treatment with the BRD4 inhibitor JQ1 conferred renoprotection and downregulated NOX4. Mechanistically, chromatin immunoprecipitation assays demonstrated that upon LPS stimulation, BRD4 is recruited to the NOX4 promoter, facilitates the co-recruitment of the histone acetyltransferase P300, and promotes local histone H3 acetylation to directly activate NOX4 transcription. Importantly, NOX4 overexpression delivered by AAV, which was predominantly detected in renal tubules, largely abolished the protective effects of JQ1, indicating that NOX4 is a critical downstream target of BRD4. In conclusion, our findings identify the BRD4/P300/NOX4 transcriptional regulatory axis as a key pathogenic mechanism in S-AKI, offering a novel therapeutic insight for this condition.