BRD4 promotes LPS-induced endothelial cells senescence via activating and cooperating STING-IRF3 pathway.

Endothelial cells (ECs) senescence is closely associated with the initiation and development of multiple age-related cardiovascular diseases. It is necessary to explore the underlying molecular mechanisms of ECs senescence, which is not only the basis to decipher cellular senescence, but also a novel therapeutic target for the endothelial senescence-related diseases. BRD4, a key epigenetic regulator, is universally related to gene expression regulation and has been reported to accelerate cell senescence. Besides, emerging evidence has suggested that the stimulator of interferon genes protein (STING) can regulate inflammatory and senescence-related diseases. However, whether STING pathway activation is regulated by BRD4 in the context of ECs senescence remains largely unclear. Here, we observed that elevated BRD4 and activated STING-IRF3 signaling pathway during ECs senescence and further confirmed that BRD4 could abolish STING activation. We demonstrated that BRD4 could inhibit E3 ubiquitin ligase HRD1-mediated ubiquitination degradation of STING via inhibiting HRD1 transcription. In addition to the direct regulatory effect of BRD4 on STING activation, we have confirmed that BRD4 cooperates with IRF3 and P65 to promote SASP gene expression, thereby accelerating ECs senescence. Here, we proposed a novel mechanism underlying BRD4' key dual role in activating the STING pathway during ECs senescence.