STING activation in cardiomyocytes drives hypertrophy-associated heart failure via NF-κB-mediated inflammatory response.

Accumulating evidence highlights the key importance of innate immunity in heart hypertrophy and failure. Though stimulator of interferon genes (STING) is an integral innate immunity regulator, whether cardiomyocyte-derived STING driving cardiac hypertrophy and failure has rarely been explored, nor has its underlying mechanism been clarified. Herein, we addressed these two questions through several mouse experiments. Our results revealed that cardiac tissues from patients exhibiting cardiac hypertrophy markedly increased STING expression. Myocardial tissues of mice challenged with angiotensin II (Ang II) or transverse aortic constriction (TAC) also showed that STING was consistently upregulated and activated. Activation of STING by cGAMP or DMXAA resulted in cardiomyocyte hypertrophy in vitro, which was abolished by STING knockout. Furthermore, deleting or pharmacologically inhibiting STING attenuated cardiac hypertrophy and dysfunction in TAC or Ang II-treated mice. In contrast, mice with cardiomyocyte-specific STING activation developed cardiac hypertrophy and failure. Mechanistically, NF-κB signaling but not TBK1 or autophagy formation was implicated in STING -induced cardiac hypertrophy and failure. Collectively, we identified that STING-NF-κB axis mediated inflammatory response to drive cardiac hypertrophy-associated heart failure, highlighting its promise as a potential therapeutic target in clinical practice.