Nucleic acid sensing pathways in kidney disease development

Sterile inflammation triggered by mislocalized self-nucleic acids has emerged as an important mechanism linking cellular injury to progressive kidney dysfunction. Among the key molecular pathways implicated in this response, those underlying nucleic acid sensing represent a central signalling mechanism, particularly the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). In both glomerular and tubular compartments, mitochondrial dysfunction, genotoxic stress and epigenetic dysregulation lead to the accumulation of cytosolic nucleic acids, including mitochondrial DNA and RNA, nuclear DNA fragments and reactivated endogenous retroelements. These signals converge on nucleic acid sensors, including STING, absent in melanoma 2 (AIM2) and endosomal Toll-like receptors (TLRs), activating proinflammatory cascades, cell death programmes and fibrotic remodelling. The latest research highlights the context-dependent engagement of these pathways across human kidney disease and in experimental models of acute kidney injury and chronic kidney disease, linking cellular damage to immune activation and fibrosis. Here, we synthesize emerging insights into the molecular programming of nucleic acid sensing in kidney disease and evaluate the therapeutic landscape, outlining opportunities and challenges for clinical translation.