The mtDNA–cGAS–STING Axis in Acute Kidney Injury and Maladaptive Repair: Preclinical Evidence for Traditional Chinese Medicine and Natural Product-Based Interventions

Abstract: Acute kidney injury (AKI) is a heterogeneous syndrome characterized by substantial variation in etiology, clinical course, and recovery. Persistent tubular stress, mitochondrial dysfunction, and dysregulated inflammatory and immune responses can prolong tissue injury and lead to incomplete kidney recovery and maladaptive repair. When released into the cytosol, mitochondrial DNA (mtDNA) can activate cyclic GMP–AMP synthase (cGAS), which generates 2′,3′-cGAMP and activates stimulator of interferon genes (STING). Downstream TBK1–IRF3 and NF-κB signaling programs amplify inflammation, regulated cell death, and failed repair. This structured narrative review follows the sequence of mitochondrial injury, mtDNA release, cGAS–STING activation, inflammation and regulated cell death, and maladaptive repair. We examine how these mechanisms vary across AKI etiologies, cell types, and disease stages and critically appraise preclinical evidence for traditional Chinese medicine (TCM) formulas and preparations, bioactive fractions and extracts, isolated natural products, and natural product-based delivery systems. Genetic and pharmacological studies support the involvement of this axis in selected AKI models. However, the mitochondrial origin of cGAS-sensed cytosolic DNA, the requirement for cGAS–STING signaling in observed protective effects, and the relevance of these mechanisms to human AKI remain incompletely established. Most TCM and natural product studies use cisplatin models and initiate treatment before or at the time of injury; they generally report parallel improvements in kidney injury endpoints and reductions in pathway-associated markers. Thus, selected interventions show preclinical renoprotective activity in specific models, but neither clinical efficacy nor in vivo pathway dependence has been demonstrated. Future translational studies should prioritize post-injury administration, causal pathway validation, kidney-compartment exposure, safety assessment, and functional testing in human-relevant systems. Keywords: acute kidney injury, mitochondrial DNA, cGAS–STING, maladaptive repair, traditional Chinese medicine, natural products