Abstract
The escalating global burden of cardiovascular disease (CVD) necessitates a deeper elucidation of the fundamental molecular mechanisms driving its pathogenesis. Aberrant immune activation, specifically sterile inflammation, is now recognized as a core hallmark of CVD, predominantly ignited by the pathological accumulation of damaged self-DNA. As the principal cytosolic DNA sensor, the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has emerged as a crucial mechanistic nexus translating genomic distress into robust innate immune responses. Despite its paramount importance, a comprehensive integration of how DNA damage-induced cGAS-STING activation orchestrates cardiovascular immunology remains underexplored. In this review, we comprehensively synthesize the dynamic immunological landscape of CVD, with a specific focus on the critical interplay between DNA damage and sterile inflammation. We delineate the intricate molecular cascades of the cGAS-STING pathway across diverse cardiovascular pathologies and critically evaluate its role as a master amplifier of disease progression. Furthermore, we highlight the translational trajectory of targeting the cGAS-STING axis, emphasizing how deciphering this DNA damage-immune network provides a rational blueprint for developing precision immunomodulatory therapies in cardiovascular medicine.