Mitochondrial dysfunction and immunoinflammatory remodeling in heart failure: Emerging role of conceptualizationthe mtDNA–cGAS/STING axis and therapeutic opportunities

Apr 17, 2026Pharmacological research

Mitochondrial Problems and Immune Changes in Heart Failure: The Possible Role of Mitochondrial DNA-Triggered Immune Response and Treatment Options

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Abstract

Mitochondrial DNA leakage during dysfunction engages the cGAS/STING pathway, amplifying inflammation in heart failure.

Persistent sterile inflammation is linked to maladaptive cardiac remodeling in heart failure.
Mitochondria have been repositioned as active players in immunometabolic signaling rather than just energy producers.
Mitochondrial DNA acts as a damage signal that triggers inflammatory responses through the cGAS/STING pathway.
Failure in mitochondrial quality control mechanisms is associated with the aberrant activation of the mtDNA-cGAS/STING axis.
This pathway contributes to a self-sustaining loop of inflammation that may worsen heart failure.
Emerging pharmacological strategies aim to target components of the mtDNA-cGAS/STING pathway for potential therapeutic benefits.

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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.

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Mitochondrial dysfunction and immunoinflammatory remodeling in heart failure: Emerging role of conceptualizationthe mtDNA–cGAS/STING axis and therapeutic opportunities

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