BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation PMID: 42014688

ADC Targets in Oncology

2026-04-10

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

Cell Death Discov. 2026 Apr 21;12(1):266. doi: 10.1038/s41420-026-03113-y.

Jing Jia ^# ¹ ² , Kangkang Ji ^# ³ ⁴ , Yong Zhou ⁵ , Yang Huang ⁶ , Ang Li ⁵ , Fan Ye ⁷ , Wen Huang ⁷ , Fang Chen ⁸ ⁹ ¹⁰ , Guoyuan Lu ¹¹

Affiliations

1. Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China.
2. Department of Nephrology, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, Yancheng Clinical Medical College of Jiangsu University, The First People's Hospital of Yancheng, Yancheng, China.
3. Department of Respiratory and Critical Care Medicine, Binhai County People's Hospital, Yancheng, China.
4. College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, China.
5. Department of General Surgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, Yancheng Clinical Medical College of Jiangsu University, The First People's Hospital of Yancheng, Yancheng, China.
6. Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, China.
7. Department of Critical Care Medicine, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, China.
8. Department of Nephrology, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, Yancheng Clinical Medical College of Jiangsu University, The First People's Hospital of Yancheng, Yancheng, China. [email protected].
9. Yancheng Key Laboratory of Molecular Epigenetics, Yancheng Medical Research Center of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China. [email protected].
10. Department of Urology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, China. [email protected].
11. Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China. [email protected].
# Contributed equally.

Abstract

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.