Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with persistent sterile inflammation emerging as a critical driver of maladaptive cardiac remodeling beyond hemodynamic stress alone. Recent advances have repositioned mitochondria from passive bioenergetic organelles to active immunometabolic signaling hubs. In this context, mitochondrial DNA (mtDNA) leakage during mitochondrial dysfunction acts as a potent damage-associated molecular pattern (DAMP), engaging the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and amplifying inflammatory cascades that accelerate cardiomyocyte loss, fibrosis, and ventricular failure. In this review, we integrate current evidence linking mitochondrial quality control failure—including oxidative stress, metabolic reprogramming, impaired mitophagy, and dysregulated mitochondrial dynamics—to aberrant activation of the mtDNA–cGAS/STING axis in HF. We further highlight how this pathway contributes to pro-inflammatory remodeling of the cardiac immune microenvironment, thereby establishing a self-sustaining immunoinflammatory loop that perpetuates disease progression. Importantly, we discuss emerging pharmacological strategies targeting this axis, ranging from mitochondrial-directed antioxidants and mitophagy enhancers to small-molecule cGAS/STING inhibitors and advanced cardiac-targeted delivery platforms. Collectively, the mtDNA–cGAS/STING pathway represents a unifying and druggable immunometabolic framework in HF, offering promising opportunities for precision anti-inflammatory intervention and therapeutic innovation. • mtDNA leakage activates cGAS/STING signaling in heart failure • Mitochondrial quality control failure drives sterile inflammation • The mtDNA–cGAS/STING axis links metabolism to immune remodeling • cGAS/STING represents a pharmacologically tractable target • Multi-level therapeutic strategies may reshape HF treatment
Zhang et al. (2026) studied this question.