# Inhibition of BRD4 activates the AKT-SIRT3 signaling pathway to suppress apoptosis and attenuate hyperoxia-induced lung injury

## TL;DR

This study shows that inhibiting BRD4 reduces lung damage from high oxygen levels by activating the AKT-SIRT3 pathway, which helps prevent cell death and inflammation.

## Contribution

The study identifies a novel role of BRD4 in hyperoxia-induced lung injury and reveals the BRD4/AKT/SIRT3 signaling axis as a potential therapeutic target.

## Key findings

- BRD4 inhibition reduces apoptosis, oxidative stress, and inflammation in hyperoxia-induced lung injury models.
- BRD4 knockdown activates AKT and upregulates SIRT3, which are essential for its protective effects.
- AKT inhibition or SIRT3 suppression reverses the protective effects of BRD4 inhibition in lung cells.

## Abstract

As a critical pulmonary complication in oxygen therapy, hyperoxia-induced lung injury (HILI) is featured with edema, alveolar wall thickening, and inflammatory cell infiltration. Bromodomain containing 4 (BRD4) has been documented as a vital regulator of apoptosis, inflammation, and oxidative stress under various pathological conditions. However, whether BRD4 plays a part in HILI has not yet been well investigated. The current investigation revealed a significant elevation of BRD4 expression in both in vitro and in vivo models of HILI. Notably, BRD4 knockdown effectively attenuated apoptosis, oxidative stress, and inflammatory response in H2O2-challenged AEC-II cells. Further investigation elucidated that BRD4 knockdown activated the AKT signaling pathway and upregulated SIRT3 expression in vitro and in vivo. AKT inhibition markedly abrogated BRD4 silencing-mediated AKT activation and SIRT3 upregulation in AEC-II cells exposed to H2O2, while SIRT3 inhibition failed to alter AKT activation. In addition, AKT inactivation also reversed BRD4 inhibition-mediated increased in the transcriptional activity of SIRT3. Furthermore, AKT inactivation or SIRT3 inhibition significantly diminished the protective effects of BRD4 knockdown on H2O2-treated AEC-II cells. In summary, this work elucidated that BRD4 inhibition ameliorates HILI through AKT-mediated SIRT3 upregulation. Our study highlights the vital role of the BRD4/AKT/SIRT3 axis in mediating HILI and suggests BRD4 as an attractive target for HILI management.