The dual role of the cGAS-STING signaling pathway in kidney diseases: from acute injury to chronic fibrosis – molecular mechanisms and precision therapeutic strategies
TL;DR
The cGAS-STING pathway has emerged as a central hub linking kidney injury to inflammation, metabolism, and fibrosis, and its precise modulation holds transformative therapeutic promise for hundreds of millions of patients with kidney diseases worldwide.
Abstract
The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses. In recent years, research on this pathway in the field of kidney diseases has expanded explosively, extending from acute kidney injury (AKI) to various pathological conditions including chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and renal cell carcinoma (RCC). This review systematically summarizes the activation mechanisms and functional diversity of the cGAS-STING pathway in different kidney diseases. In AKI, mitochondrial DNA leakage, metabolic disturbances (lipid accumulation, lactate accumulation), and post-translational modifications (e.g., LDHB K156 lactylation) collectively activate this pathway, driving sterile inflammation. In CKD and renal fibrosis, the pathway promotes metabolic reprogramming, cellular senescence, and extracellular matrix deposition through canonical (TBK1–IRF3/NF-κB) and non-canonical (STING–PERK–eIF2α) signaling axes, as well as epitranscriptional regulation (e.g., METTL3-mediated m6A modification). In DKD and LN, its overactivation mediates podocyte injury and type I interferonopathy, respectively. Of note, in RCC, this pathway primarily exerts anti-tumor immune surveillance, highlighting its highly context-dependent functions. Although preclinical studies have demonstrated the therapeutic potential of various small-molecule inhibitors (e.g., RU.521, H-151) and natural product monomers or herbal formulas, clinical translation still faces four major challenges: the dual nature of pathway function (balancing host defense versus sterile inflammation), insufficient specificity and safety of existing inhibitors, lack of predictive biomarkers for therapeutic efficacy, and drug delivery difficulties arising from renal anatomical heterogeneity. To address these bottlenecks, this review proposes next-generation precision modulation strategies, including the development of tissue/cell-specific targeted delivery systems (e.g., biomimetic nanoscavengers), application of proteolysis-targeting chimera (PROTAC) technology, intervention in upstream metabolic and mitochondrial homeostasis, modulation of post-translational modifications, and combination therapies (e.g., with SGLT2 inhibitors, immune checkpoint inhibitors, or senolytics). Finally, we discuss key future directions in this field: advancing highly selective STING inhibitors/degraders into clinical trials, establishing combinatorial biomarker panels based on urinary mtDNA/cGAMP, and achieving precision medicine stratification based on patient-specific pathway activation subtypes. In conclusion, the cGAS-STING pathway has emerged as a central hub linking kidney injury to inflammation, metabolism, and fibrosis, and its precise modulation holds transformative therapeutic promise for hundreds of millions of patients with kidney diseases worldwide.