Inflammation is a central hallmark of cardiomyopathy, where misdirected immune responses contribute to chronic myocardial dysfunction. Among the emerging molecular mechanisms implicated in this process, the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has garnered increasing attention. Acting as a key cytosolic DNA sensor, the cGAS/STING pathway orchestrates inflammatory responses triggered by microbial infections or endogenous cellular stressors such as autophagy and apoptosis. Despite its pivotal role, the precise molecular mechanisms regulating this pathway and its role in cardiomyopathy-associated inflammation remain poorly understood and subject to ongoing debate. To address this scientific gap, we first reviewed key findings on cGAS/STING signaling in various forms of cardiomyopathy, drawing from in vivo and in vitro studies, as well as clinical samples. In the next step, we explored how the cGAS/STING pathway could be modulated by specific agonists and antagonists in the context of cardiac disease. Finally, by integrating publicly available human single-cell RNA sequencing (scRNA-seq) data and a systematic literature review, we identified existing molecular interventions and highlighted promising therapeutic targets aimed at mitigating cGAS/STING-driven inflammation. This comprehensive approach emphasizes the therapeutic potential of targeting the cGAS/STING pathway and provides a foundation for developing novel interventions aimed at alleviating inflammatory cardiomyopathy and improving patient outcomes. Future studies will be essential to validate these findings and facilitate their translation into clinical practice.

Inflammation is a key hallmark in cardiomyopathy where misdirected immune activation causes chronic myocardial dysfunction. Among the emerging mechanisms implicated in the dysfunction, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling pathway has attracted significant attention. Acting as a critical DNA sensor, the cGAS/STING pathway coordinates inflammatory responses triggered by microbial invasions or endogenous stressors such as autophagic or apoptotic cell death. Despite its pivotal role, the precise molecular mechanisms regulating this pathway and its contribution to aberrant inflammation in cardiomyopathy remain poorly understood and controversial. To address this scientific gap, we first summarized the key findings on the cGAS/STING pathway in different cardiomyopathies using in vivo/in vitro models as well as clinical samples. In the next step, we explored how the cGAS/STING pathway could be modulated by it agonists and antagonists in cardiomyopathy. Finally, leveraging publicly available human single-cell ribonucleic acid sequencing (RNA-seq) dataset and systematic literature review, we identified existing molecular interventions and highlighted potential therapeutic targets to mitigate cGAS/STING-driven inflammation. This integrative approach underscores the therapeutic potential of targeting the cGAS/STING pathway and provides a foundation for developing novel interventions aimed at alleviating inflammatory cardiomyopathy and improving patient outcomes. Future studies will be crucial in validating these findings and translating them into clinics.