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

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 <i>in vitro</i> and <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i>. 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.