The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration

Zheng Wu; Rong-Jun Jia; Qi Zhang; Li-Yan Huang; Jun-Ting Yan; Yan-Hui Zhang; Yong-Gang Fan

doi:10.1186/s40364-026-00906-2

. 2026 Feb 16;14:34. doi: 10.1186/s40364-026-00906-2

The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration

Zheng Wu ^1,^2,^#, Rong-Jun Jia ^2,^#, Qi Zhang ^2,^#, Li-Yan Huang ², Jun-Ting Yan ², Yan-Hui Zhang ^3,^✉, Yong-Gang Fan ^1,^✉

PMCID: PMC13015178 PMID: 41699746

Abstract

Mounting evidence indicates that aging and neurodegenerative diseases extensively interact with brain immune processes. Cyclic GMP-AMP synthase (cGAS) recognizes aberrant DNA to produce 2‘3’-cGAMP, which activates STING and subsequently induces the type-I interferon response and transcription of inflammatory factors, leading to neuroinflammation that accelerates various acute and chronic neurological disorders. In this review, we summarized the features of cGAS and STING, and depicted the mechanisms concerning exogenous DNA, mitochondrial DNA, nuclear DNA, and protein phase separation in activating the cGAS-STING pathway. Moreover, the multifunctional roles of the cGAS-STING pathway in aging and neurological disorders were highlighted, and the known cGAS or STING inhibitors for the therapy of neurological disorders were discussed. This review summarizes the intricate interplay between the cGAS-STING pathway and neurodegenerative diseases, underscoring its pivotal role in neurodegenerative processes and brain health.

Graphical Abstract

graphic file with name 40364_2026_906_Figa_HTML.jpg — The cGAS-STING pathway at the crossroads of neuroimmunology: Bridging innate immunity to aging and neurodegeneration

Keywords: cGAS-STING axis, aging; neurodegenerative diseases, Phase separation, Inhibitors

Introduction

Neurodegenerative diseases (NDs) are a group of central nervous system (CNS) disorders primarily associated with neuronal damage manifested as cognitive and/or behavioral dysfunction [1]. Many NDs can progress to dementia, which is projected to affect approximately 150 million people worldwide by 2050, with an economic burden of $10 trillion and incalculable costs to patients and their families [2]. To date, no effective therapeutic approaches have been developed to slow down, stop, or prevent any NDs, as the etiology involved is too complex, such as genetic, environmental, metabolic, and immune factors, and the combined effect of these factors. Therefore, research on the therapeutic targets associated with NDs has been at the forefront of academic research.

The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are the main signaling pathways in vertebrates, activating the host’s innate immunity against DNA-containing pathogens or abnormal DNA [3]. They are closely related to chronic inflammation and cellular senescence and the development and progression of most NDs, such as Alzheimer’s disease (AD) [4], and are key drivers of chronic inflammation and functional decline during aging [5]. Exogenous pathogens or self-injurious DNA can activate microglia, initiating the cGAS-STING signaling pathway and triggering neuronal antiviral defense mechanisms. In turn, over-activation can lead to neuroinflammation and common NDs, including AD, Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and stroke [6, 7]. In recent years, animal experiments and human clinical studies have shown that regulating this pathway can improve related disease states [8, 9].

In this review, we have outlined the immune activation mechanism mediated by the cGAS-STING pathway, summarized its association with chronic inflammation, cellular senescence and various NDs, and listed the current research on cGAS-STING related inhibitors, discussing their therapeutic significance.

The characteristics of the cGAS-STING pathway

Mammalian immune defense has two important components, the innate immune system and the adaptive immune system. Among them, innate immunity recognizes biomolecules through pattern recognition receptors (PRRs). These include metabolism-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) [10, 11]. PRRs are genetically intrinsic to recognizing conserved ligands from pathogens, as well as host factors released during pathogen infection and tissue injury. Many PRRs have evolved to recognize conserved basic components of pathogens (most often the pathogen component is their genetic material, consisting of either DNA or RNA), and are thus able to respond to a large range of pathogens [12]. Except that, the cGAS-STING pathway is a crucial component of innate immunity [13].

cGAS

cGAS is a cyclic GMP-AMP (cGAMP) synthase belonging to the nucleotidyl transferase family, consisting of an N-terminal disordered structural domain and a C-terminal catalytic structural domain [14]. Human cGAS (hcGAS), also known as C6ORF150 or MB21D1, has a molecular weight of approximately 60 kDa and is composed of 522 amino acids. It contains a disordered N-terminal structural domain and a C-terminal catalytic structural domain. The N-terminal structural domain consists of amino acids 1–160 and contains a high density of positively charged amino acid residues, which are required for the binding of double-stranded DNA (dsDNA) [15–18]. cGAS is primarily reported to be present in the cytoplasm; however, it has also been found in the mitochondria, plasma membrane, and especially abundantly in the nucleus (Fig. 1). The localization at the plasma membrane is particularly notable for its role in detecting microorganisms promptly upon their entry into the cell [19, 20].

Fig. 1 — Subcellular localization of cGAS. A. cytosolic cGAS primarily originates from two sources: de novo synthesis through ribosomal translation and nuclear export via the NES of cGAS. The amino acids 1–212 in the N-terminal domain of cGAS are essential for its retention in the cytosol, while the phosphorylation of tyrosine 215 enhances cytosolic retention by blocking nuclear import. B. cGAS enters the nucleus through two pathways: passive diffusion during NE breakdown and active transport via the NLS located in both the C- and N-terminal domains of cGAS. Within the nucleus, cGAS binds to the AP of the H2A-H2B dimer in nucleosomes, forming a cGAS-nucleosome 2:2 complex. C. cGAS is anchored to the plasma membrane through electrostatic interactions between the negatively charged phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) and the highly positively charged N-terminal domain of cGAS (PDB ID: 4LEV). D. proteolytic processing or structural changes in cGAS can remove the N-terminal domain (amino acids 1–160) that masks the mitochondrial targeting signal (MTS). This removal leads to mitochondrial localization and activation of cGAS. aa: amino acid; AP: acidic patch; ER: endoplasmic reticulum; MTS: mitochondrial targeting signal; NES: nuclear export signal; NLS: nuclear localization signal; PI(4,5)P2: phosphatidylinositol 4,5-bisphosphate. The figure was created with BioRender.com

cGAS is primarily known for its role in detecting cytosolic DNA, thus triggering the immune response. Beyond cytosolic DNA sensing, cGAS is also localized in the nucleus and serves as a guardian of chromatin integrity and a sensor for nuclear threats. cGAS could enter the nucleus through passive diffusion via nuclear envelope (NE) breakdown, and active import via the nuclear localization signals (NLS) in the N- and C-terminus [21]. In the nucleus, the C-terminal domain of cGAS binds to the nucleosomes via the H2A-H2B acidic patch (AP), anchoring itself to chromatin. Studies have revealed that the N-terminal domain (amino acids 1–160) of cGAS contains a highly positively charged region that selectively binds to the negatively charged phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂), a lipid enriched in the plasma membrane [20]. Fusion of the N-terminus to the mislocalized cGAS mutants would restore the plasma membrane localization, which highlights that the N-terminus is the necessary and sufficient structure for membrane targeting [20]. Tethering cGAS to PI(4,5)P₂-rich membranes could spatially separate cGAS from nuclear/mitochondrial DNA, reduce the autoactivation by self-DNA, while the membrane-localization hinders the dimerization and DNA binding of cGAS, reducing the responsiveness to viral DNA compared to cytosolic cGAS, so the release from the membrane is essential for the activation of cGAS [20].

Recent studies also identify the presence of cGAS in the mitochondria. The N-terminal domain (amino acids 1–160) of hcGAS masks a mitochondrial targeting signal (MTS), and removing the first 160 amino acids would expose the MTS, leading to the mitochondrial localization and activation of cGAS [22]. The proteolytic processing or structural changes of cGAS would induce its mitochondrial localization. In contrast, cGAS is not typically active inside mitochondria; the classical pathway of its activation is primarily associated with the release of mitochondrial DNA (mtDNA) triggered by the increased permeability of mitochondrial-associated membranes (MAMs). Although the functional significance of cGAS mitochondrial localization remains unclear, the important role in detecting mtDNA leakage or coordinating stress responses warrants further investigation.

cGAS can be activated by endogenous and exogenous DNA, including invading pathogen DNA, mitochondrial DNA, micronuclei (MNi) DNA, genomic DNA, etc (Fig. 2). cGAS senses dsDNA and incomplete nucleoidal or curved DNA in a length-dependent but sequence-independent manner [18], but cGAS has a much weaker binding affinity for single-stranded DNA (ssDNA) [15, 23]. The dsDNA binds to the platform between the spiny helix and zinc finger structure of cGAS to form a 2:2 dimer or highly ordered complex. The cGAS dimers then form a ladder network structure, head-to-head close to the DNA, leading to activation of cGAS [18, 24]. Upon binding to DNA, cGAS can then undergo a conformational change that results in a rearrangement of the enzyme’s catalytic pocket, which permits the binding of adenosine-5’-triphosphate (ATP) or guanosine triphosphate (GTP) for further synthesis of the second messenger cGAMP [18, 25]. Intracellular cGAMP can be released into the extracellular space through transmembrane channels or in the form of extracellular vesicles that are directly sensed. It has also been found that cGAMP can be delivered through intercellular junctional proteins that form gap junctions with neighboring cells as well as through extracellular vesicles [26–29].

Fig. 2 — The activation model of cGAS and STING. cGAS (PDB ID: 5N6I) is activated by double-stranded DNA (dsDNA), which includes exogenous DNA from viruses, dying cells, and tumor cells, as well as endogenous DNA derived from mtDNA, micronuclei DNA, and retroviral reverse transcription DNA. STING (PDB ID: 4KSY) is activated by CDNs, which are second messengers found in both bacteria and mammalian cells. In bacteria, the CDNs include cyclic di-GMP (PDB ID: 4F9G), cyclic di-AMP (PDB ID: 8HWJ), and 3‘3’-cGAMP (PDB ID: 4KSY). In mammalian cells, the CDN is 2‘3’-cGAMP (PDB ID: 8T5L). cGAS, cyclic GMP-AMP synthase; CDNs, cyclic dinucleotides; cGAMP, cyclic GMP-AMP; mtDNA: mitochondrial DNA; STING, stimulator of interferon genes. The figure was created with BioRender.com

STING

STING, also known as TMEM173, MITA, MPYA, and ERIS, belongs to the endoplasmic reticulum (ER) membrane proteins, contains 379 amino acids and has a molecular weight of about 40 kDa, which are composed of a short cytoplasmic N-terminal segment, a four-spanning transmembrane structural domain, a linker region, and a cytoplasmic ligand-binding structural domain (LBD) [30]. In the course of screening for Type I interferon (IFN-I) response mediators, several research groups independently identified a protein, called STING, that is activated by DNA and up-regulates the IFN-I response. Scholars initially thought STING could directly detect cytoplasmic DNA and trigger a chain reaction. Subsequently, it was discovered that the ligand for STING is cyclic dinucleotide (CDN), not DNA [31, 32] (Fig. 2). In addition to its participation in intrinsic immune-related activities, STING has other regulatory functions in cellular physiology, such as the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths [33]. STING is primarily involved in two distinct downstream signaling cascades. The first is the evolutionarily conserved STING antiviral function. The second is the induction of activation of innate immune transcription genes. Regardless of the pathway, STING is ultimately degraded in the lysosome [34–37].

The effect of STING activation depends on the specific activation context, including the cell type involved, the cell death pathway activated, and the extent and duration of activation. Upon binding to cGAMP, STING, the binding ligand, undergoes a substantial conformational change to a tetrameric or higher oligomeric structure that migrates to the ER-Golgi intermediate compartment (ERGIC) or Golgi apparatus. The activation of STING and its subsequent translocation from the ER to the Golgi apparatus are considered critical steps in signal transduction. Through TANK-binding kinase 1 (TBK1), C-terminal tail (CTT) and interferon regulatory factor 3 (IRF3), the expression of IFN-I is induced [38, 39]. Newly secreted IFN-I induces dimerization of interferon alpha receptor 1 (IFNAR1) and IFNAR2, which triggers autophosphorylation of the receptor-associated protein tyrosine kinase Janus kinase 1 (JAK1), which further activates signal transducer and activator of transcription 1 (STAT1) and STAT2. Phosphorylated STAT1 and STAT2 dimerize with interferon regulatory factor 9 (IRF9) to form a three-molecule complex: interferon-stimulated gene(ISG) factor 3 (ISGF3), which binds to interferon-stimulated response element (ISRE) in the nucleus to activate transcription of ISGs, which act as a defense against infection by inhibiting viral replication and degrading viral nucleic acids [40, 41]. In addition to IFN-I, STING stimulates NF-κB-mediated transcription to increase inflammatory cytokines and chemokines, although the specific activation of this mechanism has not been elucidated yet [42–44] (Fig. 3).

Fig. 3 — Activation of the cGAS-STING signaling pathway. The positively charged N- and C-termini of cGAS bind to negatively charged DNA, which stimulates the production of cGAMP. cGAMP then binds to and activates STING, a protein located in the endoplasmic reticulum (ER). Once activated, STING translocates to the Golgi apparatus, where it recruits and activates TBK1 and IKK. These kinases then phosphorylate IRF3 and release NF-κB dimers, respectively, facilitating the translocation of IRF3 and NF-κB into the nucleus. In the nucleus, IRF3 and NF-κB dimers bind to specific DNA sequences, regulating the transcription of interferons (IFNs). When IFNs bind to their receptors, this activates the receptor, causing JAKs activation (Janus kinases, specifically JAK1 and TYK2, come into close proximity and phosphorylate one another). Activated JAKs then phosphorylate tyrosine residues on the receptor, forming a receptor complex that serves as a docking site for STAT proteins (signal transducer and activator of transcription). The receptor complex recruits and activates STAT proteins, which then dimerize and bind to IRF9, forming the ISGF3 complex. This complex translocates to the nucleus, leading to the expression of interferon-stimulated genes. ER: endoplasmic reticulum; IFNs: type I interferons; IKK: IκB kinase; IRF3: interferon regulatory factor 3; IRF9: interferon regulatory factor 9; ISGF3: interferon-stimulated gene factor 3; JAKs: associated Janus kinases; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; STAT: signal transducer and activator of transcription; TBK1: TANK-binding kinase 1. The figure was created with BioRender.com

The cGAS-STING pathway recognizes DNA released by infection and cellular damage and promotes the release of chemokines and cytokines, triggering a series of downstream cascade responses [15, 45, 46]. When the nucleus or mitochondria are damaged or infected by viruses, DNA fragments are released from the cell. cGAS recognizes as well as binds to these DNA fragments and catalyzes the production of a second messenger, the 2‘3’-cGAMP [15, 47–49]. When cGAMP is detected, STING proteins located in the ER dimerize, and the STING dimer undergoes further structural and conformational changes leading to oligomerization and self-activation [50, 51]. Thus, the cGAS-STING pathway is a key mediator of inflammation that can be activated by cGAS, which in turn mediates STING protein-driven innate immune activation.

Regulatory networks of the cGAS-STING pathway

Exogenous viral DNA-mediated activation of the cGAS-STING pathway

Organisms face constant attacks from pathogens. To survive, hosts must resist and eliminate these threats. Pathogen-derived nucleic acids, such as ssDNA, dsDNA, RNA, and RNA-DNA hybrids, can be detected by host cell sensors, triggering innate immune responses [18, 52]. The viral RNA infection is mainly sensed by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), while the viral DNA infection is mainly sensed by widely expressed cGAS [53–55]. The viral DNA can activate both the cytosolic cGAS and the nuclear cGAS. Normally, the cytosolic cGAS detects viral DNA and forms liquid-like condensates via liquid-liquid phase separation (LLPS) [56], which enables the efficient synthesis of the second messenger 2‘3’-cGAMP, and triggers STING-dependent IFN responses. The IFN-mediated defense induced by the cGAS-STING pathway is the critical antiviral step, and downstream PRRs facilitate this process by further amplifying immune signaling (e.g., JAK-STAT pathway) [57, 58]. Additionally, emerging research has shown that the viral DNA triggers the activation of the nuclear DNA sensor cGAS via perturbing centromeric stability in host cells, which subsequently leads to centromeric DNA amplification [59]. However, viruses have evolved various mechanisms to evade the cGAS-STING pathway activation. Herpesviruses (e.g., Kaposi’s sarcoma-associated herpesvirus, KSHV; herpes simplex virus 1, HSV-1; varicella-zoster virus, VZV) encode tegument proteins (ORF52/VP22 family) that disrupt cGAS-DNA phase separation. ORF52/VP22 proteins can form their own LLPS with DNA, competitively displacing cGAS from DNA; thus, the disruption of cGAS-DNA droplets would reduce cGAMP production and dampen IFN responses [56]. In addition, the virus can also counteract this immune detection by expressing UL36USP, a deubiquitinase that suppresses translesion DNA synthesis, thereby preventing centromeric DNA amplification and cGAS activation [59].

Viral infections induce reactive oxygen species (ROS) production and mediate apoptosis, which reduces the host’s antiviral capacity and promotes viral infections, exacerbating the disease process [60, 61]. However, in some other studies, oxidative stress somewhat activated the antioxidant defense system and autophagy in tissues and organs, which helped to scavenge some ROS and induced stress defenses [62]. In this process, cGAS-STING is a potential target for linking oxidative stress to viral infection.

mtDNA-mediated activation of the cGAS-STING pathway

MtDNA is a circular, double-stranded molecule enclosed within the mitochondrial matrix by the inner (IMM) and outer (OMM) membranes, where it encodes essential oxidative phosphorylation proteins [63]. Under physiological conditions, mtDNA stability is maintained through multiple mechanisms (Fig. 4): (1) Mitochondrial transcription factor A (TFAM) mediates mtDNA packaging and replication initiation; (2) the DNA Polymerase γ (POLγ), two novel mutations in PEO1 (TWINKLE), and ssDNA-binding protein (SSBP1) complex ensures accurate replication; (3) base excision repair (BER) and double-strand break repair counteract oxidative damage; (4) intact mitochondrial permeability transition pore (mPTP), pro-death proteins (e.g., BAX, BAK) and voltage-dependent anion channel (VDAC) pores prevent membrane permeabilization; (5) balanced fission (dynamin related protein 1, Drp1) and fusion (optic atrophy 1, OPA1; mitofusin-1, MFN1; mitofusin-2, MFN2) preserve mitochondrial structure; and (6) mitophagy and TFAM-LC3B-mediated autophagy clear damaged mtDNA. Additionally, mitochondrial-derived vesicles (MDVs) sequester mtDNA, while cristae stability factors (OPA1; prohibitin 1, PHB1; sorting and assembly machinery 50, SAM50) restrict mtDNA exposure. These safeguards collectively prevent c mtDNA leakage and aberrant cGAS-STING pathway activation.

Fig. 4 — Factors contributing to mitochondrial DNA stability under physiological conditions. A. mtDNA is confined within the mitochondrial matrix, the IMM and OMM act as physical barriers that isolate mtDNA from cytosolic cGAS. B. the proteins POLγ, TWINKLE, and SSBP1 form the core replication machinery for mtDNA replication, ensuring proper replication. POLγ is the sole mtDNA polymerase that extends RNA primers, TWINKLE unwinds the mtDNA double helix, allowing replication to occur, and SSBP1 stabilizes the displaced single-stranded mtDNA during this process. Additionally, TFAM binds to and condenses mtDNA, which aids in the initiation of replication and protects mtDNA from cellular stress, thereby maintaining its integrity. Because mtDNA is more vulnerable than nuclear DNA, the repair processes are crucial for maintaining mtDNA stability. Double-strand break repair and base excision repair are the primary mechanisms for repairing damaged mtDNA. C. the IMM-resident mPTP remains closed, the OMM-resident BAX/BAK oligomerization macropores and VDAC oligomer pores stay inactive under physiological conditions. GSDMD, which initially resides in the cytoplasm, does not translocate to the mitochondrial membrane. This maintenance helps preserve the structural integrity of both the IMM and OMM and prevents the release of mtDNA. D. the IMM is folded into cristae, and its structural stability is regulated by several factors, including OPA1, PHB1, SM50, and mitofilin. The mPTP, a channel in the IMM, plays a role in regulating the shape and function of the cristae. E. MDVs are small vesicles that bud off from mitochondria, shuttling mtDNA within them. The integrity of these MDVs prevents mtDNA from accessing the cytoplasm. F. the balance between mitochondrial fusion and fission is crucial for maintaining mtDNA integrity. Fission, primarily regulated by Drp1, is the process of dividing mitochondria, while fusion, regulated by OPA1, MFN1, and MFN2, involves the merging of mitochondria. G. the degradation of mtDNA serves as a protective mechanism against the accumulation of damaged mtDNA. This process includes (a) mitophagy-induced degradation, where damaged mitochondria are recognized and engulfed, and (b) TFAM acting as an autophagy receptor and interacting with LC3B to facilitate the autophagic degradation of cytosolic mtDNA. All these factors collectively contribute to mtDNA stability, preventing it from leaking into the cytoplasm and activating cGAS. BNIP3: BCL2/adenovirus E1B 19-kDa interacting protein 3; DRP1: dynamin-related protein 1; FUNDC1: FUN14 domain-containing protein 1; GSDMD: gasdermin D; HR: homologous recombination; IMM: inner mitochondrial membrane; MDVs: mitochondrial-derived vesicles; MFN1/2: mitogenic protein 1/2; MMEJ: microhomology-mediated end joining; mPTP: mitochondrial permeability transition pore; OMM: outer mitochondrial membrane; OPA1: optic atrophy protein 1; PINK: PTEN-induced kinase 1; POLγ: polymerase γ; SSBP1: single-stranded DNA-Binding protein 1; TFAM: mitochondrial transcription factor A; VDAC: voltage-dependent anion channel. The figure was created with BioRender.com

mtDNA is more susceptible to damage than nuclear DNA, and when this happens, the damaged mtDNA can leak into the cytoplasm and further trigger interferon and inflammatory responses [64]. Under pathological conditions, mtDNA stability can be disrupted via multiple routes: (1) replication/repair defects (e.g., TFAM depletion or POLγ dysfunction) [65–67]; (2) membrane disruption (BAK/BAX oligomerization, mPTP opening, or GSDMD-NT pore formation) [68, 69]; (3) cristae destabilization (OPA1/SAM50/PHB1 downregulation); (4) excessive fission (Drp1 overactivation) or fusion impairment (MFN1/MFN2 deficiency); (5) MDV degradation; and (6) failure to remove damaged mitochondrial (Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1)/Parkin or autophagosome-lysosome defects). The cytosolic mtDNA binds cGAS, triggering LLPS and 2‘3’-cGAMP production, which activates STING-dependent interferon and inflammatory responses [14, 70–72]. Notably, ROS-induced mtDNA damage (from electron transport chain leakage) and nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome activation (via interleukin 1, IL-1β secretion) further amplify mtDNA release and cGAS-STING signaling, creating a pro-inflammatory feedback loop [72, 73].

Nuclear DNA-mediated activation of the cGAS-STING pathway

Contrary to its initial characterization as a predominantly cytosolic DNA sensor, emerging evidence demonstrates robust nuclear localization of cGAS [14, 73–76]. Cells strictly prevent nuclear DNA leakage into the cytoplasm and the nuclear cGAS activation through various mechanisms under physiological conditions (Fig. 5). The nuclear DNA resides within the nucleus by the nuclear membrane (NM), which forms a physical barrier that separates DNA from the cytoplasm. Even during mitosis, the NE can reform to re-establish the nucleocytoplasmic barrier to ensure proper compartmentalization of the nucleus. Additionally, the nuclear pore complexes (NPCs) on the NM prevent DNA from passing through freely [77]. Although NM breakdown can occur during nuclear lamina defects, cellular stress, or cell division, rapid repair typically restores integrity within minutes [77]. In cases of acute NE disruption, barrier-to-autointegration factor (BAF) competitively binds DNA, preventing its interaction with cGAS. Notably, BAF downregulation triggers an ISG response, highlighting its critical role in regulating cGAS and suppressing aberrant innate immune activation [78]. Pathological conditions disrupt these protective mechanisms through (Fig. 6): (1) failure to recruit/inactivate membrane remodeling complexes (endosomal sorting complexes required for transport, ESCRT; BAF; lap2b-emerin-man1, LEM domain proteins); (2) polyQ aggregate interference with NE repair [79]; and (3) formation of fragile micronuclei and chromatin bridges from mitotic errors that readily rupture [80]. These events expose nuclear DNA to cytoplasmic cGAS, triggering STING pathway activation.

Fig. 5 — Schematic diagram of nuclear DNA stability maintenance under physiological conditions. Under physiological conditions, A. nuclear DNA is contained within the nucleus, surrounded by the nuclear membrane (both the INM and ONM). The structure of the NE is supported by the nuclear lamina. B. during mitosis, the NE breaks down to allow for chromosome segregation. After this process, the NE reforms to re-establish the nucleocytoplasmic barrier, ensuring proper compartmentalization of the nucleus. C. NE rupture can be triggered by defects in the nuclear lamina, cellular stressors, or Mechanical stress. This disruption compromises the separation between the nucleus and cytoplasm, exposing genomic DNA to the cytoplasm. While cells can recruit membrane remodeling complexes to the rupture site to reseal the NE and restore nuclear compartmentalization within minutes. D. (a) cGAS binds to the negatively charged assembly product (AP) formed by histones H2A and H2B. This interaction, which involves specific arginine residues on cGAS, facilitates the chromatin tethering of cGAS and inhibits its catalytic activity. (b) During mitosis, AURKB and CDK1 phosphorylate multiple serine/threonine sites within the C- and N-terminal domains of cGAS, subsequently deactivating its enzymatic activity. Additionally, SUV39H1-mediated methylation at K362 of cGAS can stabilize its tethering to chromatin. The figure was created with BioRender.com

Fig. 6 — Nuclear DNA cytosolic leakage during physiological stress. A. the failure of inactivation or recruitment of membrane remodeling complexes leads to incomplete repair of the NE, resulting in persistent ruptures and DNA leakage. Moreover, polyQ aggregates can also cause NE rupture and interfere with the repair process. B. the NE of micronuclei, which result from cell division errors, is weak and particularly prone to irreparable ruptures, exposing the micronuclear DNA to the cytoplasm. C. chromatin bridges may form when chromosomes or fragments pull toward opposite poles but do not separate completely. If these bridges break due to nuclear membrane rupture or Mechanical stress, it can result in broken chromosomes and DNA damage. D. (a) RNase H2 functions as an enzyme that degrades the RNA component of R-loops. A deficiency in RNase H2 leads to persistent R-loops, disrupting transcription, causing DNA damage, and activating the immune response. (b) Nuclear stress and displacement by the MRN complex can liberate cGAS from the chromatin, allowing it to enter the nuclear soluble fraction and activate subsequently. AP: acidic path; AURKB: aurora kinase B; CDK1: cyclin-dependent kinase-1; INM: inner nuclear membrane; MRN: Mre11-Rad50-Nbn; NE: nuclear envelope; ONM: outer nuclear membrane; polyQ: polyglutamine protein; SUV39H1: suppressor of variegation 3–9 homolog 1. The figure was created with BioRender.com

The activity of nuclear cGAS is tightly regulated through chromatin sequestration and post-translational modifications (PTMs), ensuring its inactivation under physiological conditions. Nuclear cGAS binds to chromatin via its C-terminal domain, which interacts with the H2A-H2B AP, forming 2:2 complexes that sterically block DNA-binding sites and inhibit cGAS dimerization and activation [37, 73, 81]. Additionally, cyclin-dependent kinase 1 (CDK1)/aurora kinase B (AURKB)-mediated phosphorylation during mitosis suppresses cGAS enzymatic activity [22], while suppressor of variegation 3–9 homolog 1 (SUV39H1)-dependent methylation at K362 (in humans) recruits ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to further stabilize chromatin tethering [82]. However, under pathological conditions, nuclear stress or displacement by the Mre11-Rad50-NBS1 (MRN) complex can release cGAS from chromatin, allowing it to enter the nuclear soluble fraction and become activated. Furthermore, the loss of inhibitory PTMs removes these regulatory constraints, leading to cGAS activation [83].

Protein separation regulates the cGAS-STING pathway

In human tissue cells, proteins exhibit high sensitivity to stress conditions such as temperature fluctuations, nutrient availability changes, injury, or infection. Under such stresses, proteins may misfold and aggregate into insoluble precipitates [84]. Emerging evidence indicates these stressors can also drive protein phase separation (PPS), causing homogeneous protein solutions to separate into protein-rich phases [71, 85]. PPS plays a crucial role in forming biomolecular condensates known as membrane-less organelles (MLOs), which help preserve protein functionality and regulate adaptive stress responses under extreme environmental conditions to ensure cell survival [71, 85–87]. These MLOs are extensively involved in critical cellular functions, including intracellular transport, environmental sensing for homeostatic responses, and fibronectin assembly [88, 89].

Biomolecular phase separation significantly impacts multiple stages of cGAS-STING signaling, including the formation of cGAS, STING, and IRF3 condensates [90]. A previous study revealed that upon viral stimulation, IRF3 undergoes LLPS with the ISRE DNA in the nucleus, forming transcriptionally active droplet-like condensates. These condensates subsequently recruit their homologous factor interferon regulatory factor 7 (IRF7) and assemble into an efficient gene transcription hub, activating the transcription of IFN-I [91]. There are also literature studies indicating that multivalent interactions between cGAS’s DNA-binding sites and the DNA phosphate backbone drive DNA-induced LLPS of cGAS [70, 92], and this is a critical mechanism for innate immune activation. Upon binding to DNA, cGAS forms dynamic liquid-like droplets that concentrate cGAS, DNA and substrates, enhancing its enzymatic activity and innate immune signaling [70].

The formation and activity of DNA-induced cGAS LLPS are regulated by a complex interplay of multiple interconnected factors [93] (Fig. 7). First, DNA length determines LLPS efficiency, with longer DNA (e.g., 100 bp) exhibiting stronger phase separation than shorter fragments (e.g., 45 bp) due to increased binding valency. The cGAS structure itself plays a crucial role, as full-length cGAS, with its disordered N-terminus providing additional DNA-binding sites, demonstrates superior phase separation capability compared to N-terminal truncations. Zinc ions (Zn²⁺) serve as essential stabilizers by directly binding to and reinforcing the cGAS-DNA complex, enabling LLPS even at low concentrations. Salt concentration also significantly modulates this process; high salt disrupts LLPS by weakening electrostatic interactions, and physiological salt conditions can suppress cGAS activity unless Zn²⁺ is present to counteract this effect. The dynamic nature of LLPS evolves over time, progressing from initial liquid droplets that facilitate cGAS activation to more gel-like structures that limit activity after approximately 30 minutes. Although substrates like ATP and GTP become concentrated within these droplets, they do not initiate LLPS but rather optimize cGAS enzymatic activity. Specialized positive regulators further fine-tune this process: ZYG-11 family member B (ZYG11B) enhances cGAS-dsDNA affinity and condensate stability, ubiquitin-specific protease 15 (USP15) accelerates immune responses through its intrinsically disordered region (IDR)-mediated promotion of cGAS dimerization and condensation, and poly r(C) binding protein 1 (PCBP1) strengthens cGAS-DNA interactions by directly binding viral DNA [94–96]. Conversely, negative regulators such as three prime repair exonuclease 1 (TREX1), AURKB, and BAF inhibit cGAS-DNA condensate formation through distinct mechanisms: TREX1 binds and cleaves DNA 3’ ends to promote degradation, AURKB phosphorylates the cGAS N-terminus to block LLPS, and BAF clusters with DNA to prevent cGAS binding. Together, these activating and inhibitory factors constitute a sophisticated, balanced regulatory network that ensures precise spatial and temporal control of cGAS-mediated immune responses.

During DNA viral infection, cGAS activation increases cGAMP concentrations. While cGAMP has high STING affinity, excessive amounts form STING condensates that paradoxically suppress immune signaling. Interestingly, mitochondrial and Golgi-released manganese ions (Mn²⁺) promote STING phase separation and gelation by enhancing cGAMP binding. Mn²⁺ accumulation leads to cGAS-STING pathway overactivation, causing cytokine storms, cellular damage, and contributing to manganese toxicity and neurodegeneration [97, 98].

The effect of post-translational modifications on cGAS

The cGAS protein contains numerous modification sites, including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, and lactylation [99], These modifications can alter the charge properties of amino acid residues and charged sequences at multiple sites, change biomolecular size, create new binding sites, or modify local structure and conformation, which may regulate the formation and stability of phase-separated structures [100–103].

Phosphorylation

Within the cGAS-STING signaling pathway, the dynamic balance between phosphorylation and dephosphorylation of cGAS plays a decisive role in controlling its subcellular localization and activity. Studies have shown that, during specific phases of mitosis, the CDK1-cyclin B kinase complex periodically phosphorylates the S291 site of cGAS, transiently suppressing cGAMP synthesis. This modification is reversible upon cell exit from mitosis through the action of protein phosphatase 1 (PP1), restoring the DNA-sensing capacity of cGAS [83]. Further study demonstrates that cGAS activity is suppressed during mitosis through two mechanisms: one involves hyperphosphorylation of the disordered and positively charged N-terminal region by Aurora kinase B and other kinases; the other involves chromatin tethering that inhibits cGAS oligomerization. Both mechanisms prevent cGAS from undergoing phase separation into liquid droplets, thereby blocking its efficient synthesis of cGAMP. This reliable inhibition mechanism ensures cGAS remains silent during normal cell cycle progression, likely preventing autoimmune responses against nuclear DNA [22].

Acetylation

Lysine acetylation plays a crucial role in regulating chromatin structure, protein function, protein stability, subcellular localization, and gene expression [104]. Studies have found that cGAS activity is also regulated by acetylation [105, 106]. Lysine residues K47, K56, K62, and K83 in the N-terminal domain of cGAS are targets of lysine acetyltransferase 5 (KAT5)-mediated acetylation, which enhances its DNA-binding capacity and promotes cGAS-mediated immune signaling [106].

Methylation

Similar to acetylation, methylation is a crucial epigenetic modification mark on histone tails and is increasingly recognized as an important mechanism for regulating innate immunity-it influences chromatin state and DNA transcriptional activity through epigenetic pathways. Studies have confirmed that arginine and lysine residues within the cGAS-STING pathway can also undergo methylation. For instance, protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation of arginine 124 on cGAS, which inhibits its DNA-binding ability and impairs cGAS-mediated antiviral innate immune responses [107].

Ubiquitination

The dynamic regulation of protein ubiquitination primarily relies on the coordinated activity of E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). The ubiquitination of cGAS is also finely modulated by this mechanism and plays a crucial role in immune responses. Study has shown that tripartite motif protein 56 (TRIM56) induces monoubiquitination at residue K335 within the carboxyl-terminal domain (CTD) of cGAS, promoting its dimerization, enhancing DNA-binding capacity, and increasing cGAMP production [108]. Moreover, through its conserved RING-CH domain, the E3 ubiquitin ligase MARCH 8 interacts with the enzymatic core of cGAS and catalyzes the Lysine-63 (K63)-linked polyubiquitination of cGAS at lysine residues. This modification inhibits the DNA-binding capacity of cGAS, impairs cGAMP production, and attenuates downstream innate immune responses. [109].

SUMOylation

Recent studies have revealed that, beyond mediating ubiquitination, TRIM family proteins also participate in the SUMOylation of key components in the cGAS-STING pathway. SUMO modifications have been mapped to specific lysine residues (Lys335, Lys372, and Lys382) on cGAS, where they interfere with cGAS-DNA binding, oligomerization, nucleotidyl transferase activity, and phase separation, ultimately attenuating the innate antiviral response [110, 111].

Lactylation

Lactylation modification has been reported to be involved in regulating the phase separation of cGAS. L-lactate is recognized by alanyl-tRNA synthetases (AARS1/2), which act as lactyltransferases to specifically catalyze lactylation at a key N-terminal lysine residue of the cGAS protein. This modification alters the surface charge of cGAS, shifting it from a DNA-binding state to a DNA-repelling state, thereby completely inhibiting the normal liquid-liquid phase separation of cGAS with DNA. As a result, cGAS fails to form active signaling condensates, ultimately shutting down the cGAS-STING pathway and interferon production [112].

Roles and mechanisms of cGAS-STING in aging

Abnormal DNA accumulation during aging mediates the activation of the cGAS-STING pathway

Aging is characterized by decreased organismal adaptability and increased susceptibility to diseases [113]. At the cellular level, aging leads to increased cytosolic DNA from nuclear or mitochondrial sources due to genomic instability, mitochondrial dysfunction, impaired DNA repair, and declined DNA clearance [114]. These changes contribute to the accumulation of DNA damage in the CNS, a hallmark of both aging and NDs [115–117].

MtDNA leakage-induced cytosolic DNA accumulation primarily results from mtDNA mutations, epigenetic changes, mitochondrial membrane permeabilization, mitochondrial dynamics imbalance, oxidative stress, mtDNA damage, and defective mitochondrial quality control. In the context of age, mtDNA mutations not only compromise mitochondrial electron transport chain efficiency but also lead to increased electron leakage and superoxide generation, thereby elevating mitochondrial reactive oxygen species (mROS) production. The resulting oxidative stress further damages mitochondrial membranes and components, promoting mtDNA release into the cytosol [118]. Evidence from the mtDNA mutator mouse model, which expresses a proofreading-deficient version of polymerase gamma (POLG)-γ, underscores the role of mtDNA instability in aging. These animals display accelerated aging phenotypes, such as hair loss, kyphosis, markedly shortened lifespan, and metabolic and behavioral deficits, directly linking mtDNA mutagenesis to systemic aging [119]. Epigenetic modifications of mtDNA also play a critical role in age-related mitochondrial decline. Recent studies indicate that mtDNA methylation patterns shift dynamically with age, affecting the expression of mitochondrial genes and altering the binding affinity of TFAM. These epigenetic disturbances contribute to mitochondrial dysfunction, heightened oxidative stress, and deficient ATP production, establishing a vicious cycle that reinforces cellular aging [120]. Moreover, oxidative stress, a core hallmark of aging, directly damages mitochondrial integrity. It induces mPTP opening and impairs membrane stability, facilitating the leakage of mitochondrial components, including mtDNA. This process is further amplified by age-dependent dysregulation of calcium homeostasis, which lowers the threshold for mPTP activation. The consequent collapse of mitochondrial membrane potential not only disrupts ATP synthesis but also fuels additional mROS generation, creating a self-sustaining loop of oxidative damage and functional decay [121, 122]. An imbalance in mitochondrial dynamics (marked by dysregulated fission, fusion, transport, and mitophagy) also contributes to aging-related mitochondrial deterioration. With advancing age, mitochondrial biogenesis and mitophagy decline, fission-fusion equilibrium is disrupted, and oxidative phosphorylation capacity diminishes [123]. Defective mitochondrial quality control during aging contributes to dysfunctional mitochondria accumulation, which adds a burden to mtDNA leakage [124].

NE destabilization is a key contributor to DNA accumulation during aging. This process is driven primarily by three age-related mechanisms: DNA damage, nuclear pore complex (NPC) deterioration, and lamin B1 loss. Age-dependent DNA damage from both intrinsic (metabolic byproducts, free radicals) and extrinsic (UV radiation, environmental toxins) sources increases nuclear DNA burden [125]. Age-related oxidative stressors accelerate NPCs deterioration, and persistent NPCs defects lead to loss of nuclear compartmentalization [126]. The unstable lamin B1 mRNA and p53 activation during aging downregulate lamin B1, which is a critical component of the nuclear lamina, leading to the NE integrity loss and chromatin leakage [127].

The functional decline of DNA clearance also contributes to the cGAS-STING activation during aging. Senescent cells exhibit decreased deoxyribonuclease II (DNase II) and TREX1 expression, allowing DNA fragments to persist in the cytoplasm. Knockdown of DNase II/TREX1 in pre-senescent cells would induce the DNA accumulation and further activate the cGAS-STING pathway and promote senescence-associated secretory phenotype (SASP), while overexpression of DNase II/TREX1 in senescent cells can reduce DNA accumulation, thus reducing the activation of the cGAS-STING pathway and suppressing SASP [128]. Clearing senescent cells (which harbor cGAS-activating DNA), or enhancing autophagy or DNase activity (e.g., TREX1) can mitigate cytosolic DNA accumulation, and alleviate age-related inflammation [128].

cGAS-STING pathway activation exacerbates the aging and aging-related diseases

As the guardian against infection, the cGAS-STING pathway can be activated by DNA and exert the immune surveillance, while its dysregulation has also been proven to accelerate aging. The chronic activation of the cGAS-STING pathway contributes to a state of low-grade, persistent inflammation associated with aging and age-related diseases, and using compounds targeting cGAS (e.g., RU0.521), STING (e.g., nitrofuran derivatives), or TBK1 (e.g., GSK8612) reduces inflammation and improves outcomes in aging models.

At the cellular level, the cGAS-STING pathway has been implicated in exacerbating the aging process by contributing to chronic inflammation and cellular senescence. (1) cGAS-STING pathway as a driver of aging-related inflammation in peripheral organs and the brain [5]. The cGAS-STING pathway contributes to neuroinflammation in aging, potentially through its effects on microglia and astrocytes. In aged microglia, mtDNA is released into the cytosol due to mitochondrial dysfunction, a hallmark of aging. This cytosolic mtDNA activates cGAS-STING in microglia and promotes a reactive state characterized by increased expression of disease-associated microglial (DAM) and IFN-related genes. The cGAS-STING pathway also drives inflammation in peripheral organs (e.g., liver, kidney) of aged mice, contributing to tissue dysfunction, and STING inhibition can attenuate the inflammation and improve organ function [5]. (2) The cGAS-STING pathway critically regulates SASP production by detecting nuclear and mitochondrial DNA fragments. SASP propagates senescence to neighboring cells and impairs tissue function by altering intercellular communication and promoting chronic low-grade inflammation [129, 130]. Inhibition of the cGAS-STING pathway has been shown to suppress SASP gene expression in both mouse and human cells [131, 132].

At the tissue level, cGAS plays an important role in the vascular system. The expression levels of cGAS, STING, and p-IRF3/IRF3 in vascular endothelial cells increase with age, whereas the expression of the vasodilator factors, inducible nitric oxide synthase (INOS) and nitric oxide (NO), decreases in an age-dependent manner. In contrast, inhibition of the cGAS-STING pathway alleviated endothelial nitric oxide synthase (eNOS) and NO expression in mice, suggesting that modulation of the cGAS-STING pathway directly enhances vascular structure, cerebral blood supply, and reduces neurological damage in aging [133].

Age-related macular degeneration (AMD) is a vision-threatening disease characterized by progressive retinal pigment epithelial (RPE) cell death [134, 135], with aggressive choroidal neovascularization (CNV) being the primary mechanism leading to blindness [136, 137]. Inflammation plays a crucial role in the occurrence and progression of AMD [138, 139]. Shinichi Fukuda et al. found that in patients with advanced AMD, the binding of cGAS to Alu complementary DNA induces cytoplasmic mitochondrial DNA release, thereby promoting cGAS activation and triggering RPE degeneration through inflammasomes [140]. Of note, the expression levels of cGAS and STING were significantly upregulated in the RPE-choroid complex after CNV induction, and the STING inhibitor H-151 can effectively inhibit CNV development [141]. These studies highlight the vital roles of cGAS-STING signaling in regulating ADM progression.

Roles and mechanisms of cGAS-STING in NDs

Alzheimer’s disease

AD is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly, characterized by memory loss, cognitive decline, and impaired synaptic transmission due to reduced neurotransmitter levels [142–144]. The pathological mechanisms of AD involve multiple factors, including the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, oxidative stress, neuroinflammation, and disruptions in metal homeostasis [144, 145].

The cGAS-STING pathway has emerged as a key contributor to AD pathogenesis, with activation observed in both human AD brains and AD mouse models [146–148]. Research has shown that the microglia, the brain’s primary immune cells, exhibit strong cGAS-STING activation [149], and genetic deletion of STING or ataxia-telangiectasia mutated (ATM) kinase disrupts microglial chemotaxis [150]. In 5xFAD mice, a well-established AD model, cGAS interaction with cytoplasmic dsDNA was fourfold higher than that in controls, and genetic ablation of cGAS significantly ameliorated cognitive deficits, Aβ pathology, and neuroinflammation [151]. All these suggest a complex involvement of the cGAS-STING pathway in the progression of AD pathology.

cGAS-STING activation exacerbates AD through multiple pathways (Fig. 8). First, microglial exposure to toxic Aβ and hyperphosphorylated tau induces oxidative damage to mtDNA and nuclear DNA, leading to the cytoplasmic leakage of mtDNA and dsDNA fragments that activate cGAS-STING signaling and trigger neuroinflammation [152, 153]. This activation suppresses neuronal repair mechanisms mediated by myocyte enhancer factor 2c (MEF2C) [154, 155], and impairs the clearance of Aβ and tau, creating a negative feedback loop that contributes to the progression of AD. Second, cGAS-STING pathway activation in microglia upregulates the complement C3 level, then C3 marks the synapses. Microglia, which express high levels of the complement 3 receptor (C3R), recognize and bind to synapses tagged with C3b, inducing the excessive pruning of synapses and leading to the loss of functional synapses and cognitive deficits [156]. Third, cGAS activation in microglia can induce the neurotoxic A1 astrocyte phenotype [151]. Jointly release factors that are toxic to neurons and contribute to neurodegeneration; Fourth, viral infections such as HSV-1 can phosphorylate tau at AD-associated sites (e.g., S199/202, S396/404) via the cGAS-STING-TBK1 axis [157]. While the acute phosphorylation of tau induced by viral infection initially serves as a protective response to limit viral spread and preserve neurons, chronic tau phosphorylation may promote tau toxicity, mitochondrial dysfunction, and the generation of ROS, eventually exacerbating the progression of AD [157].

Parkinson’s disease

PD is an age-related neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies containing aggregated α-synuclein (α-syn) [158]. The disease manifests through both motor symptoms (bradykinesia, rigidity, tremor, and gait disturbances) and non-motor symptoms (depression, cognitive decline, and pain) [159]. Research has revealed that abnormal α-syn aggregation, propagating from the periphery to the brain, drives PD pathogenesis through multiple mechanisms, including neuroinflammation, mitochondrial dysfunction, and lysosomal impairment [159].

The inflammatory component of PD was first recognized in the 1980s with observations of microglial activation and elevated cytokines in postmortem PD brains [160, 161]. Emerging evidence indicates that α-syn preformed fibrils (PFF) can cause dsDNA breaks in microglia, activating the cGAS-STING pathway and exacerbating neuroinflammation [162]. This is supported by findings that STING-deficient mice show reduced neuroinflammation and neurodegeneration in α-syn PFF models [163, 164], and that cGAS knockout mice exhibit attenuated PD-like behaviors with preserved dopaminergic neurons and reduced microglial activation [164]. Additionally, pharmacological inhibition of cGAS (RU0.521) and STING could reduce mPTP-induced neuroinflammation [165].

The cGAS-STING pathway appears central to PD pathogenesis through multiple mechanisms (Fig. 9). Central to this process is DNA damage resulting from redox imbalance, mitochondrial dysfunction, α-syn aggregation, and excessive Mn²⁺ levels [166–168]. Responding to cytoplasmic dsDNA from damaged nuclear and mitochondrial fragments leads to the cGAS-STING pathway activation and promotes the release of pro-inflammatory factors. Furthermore, STING activation also induces GABA type A receptor-associated protein (GABARAP) lipidation, leading to leucine-rich repeat kinase 2 (LRRK2) hyperactivation that impairs lysosomal function and disrupts noncanonical autophagy [169]. Concurrently, in astrocytes, STING-mediated cytoplasmic sequestration of transcriptional factor Yin Yang 1 (YY1) derepresses Lipocalin-2 (LCN2) expression, inducing cellular senescence marked by p16^ink4a/p21 upregulation, lamin B1 loss, and elevated SA-β-gal activity [170]. These pathological changes, combined with microglia-driven neuroinflammation, synergistically promote dopaminergic neuron degeneration, highlighting the multifaceted involvement of cGAS-STING signaling in PD progression. In addition, viral infections can also contribute to the development or progression of PD by triggering neuroinflammation and potentially activating the cGAS-STING pathway [171–173].

Amyotrophic lateral sclerosis

ALS is a severe neurodegenerative disease of the CNS [174]. Its clinical symptoms can be categorized into motor and non-motor symptoms. Motor symptoms affect upper and lower motor neurons and their innervated trunk, limb, and head and face muscles, and are characterized by progressively worsening skeletal muscle weakness, myasthenia gravis, fasciculations, medullary palsy, and pyramidal signs. Non-motor symptoms manifest as social and cognitive decline, including apathy, irritability, depression, sleep disturbances, loss of empathy, and changes in eating habits [175–177]. It is particularly difficult to recognize in the early stages of the disease and can easily be diagnosed as other more common diseases, resulting in patients not receiving timely treatment [178].

Protein misfolding and aggregation are prevalent in ALS and can affect more than 90% of patients. Superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), ORF 72 on chromosome 9 (C9orf72) and optineurin (OPTN), among others, are key genetic factors that form the molecular basis of ALS [179]. TDP-43 was originally identified in 1995, and in 2006, it was found to act as a major component of ubiquitinated aggregates in ALS neurons, and abnormal aggregation of this protein can be seen in 97% of sporadic ALS cases [180]. In addition, cytoplasmic TDP-43 aggregates were seen in AD, dementia with Lewy bodies, atypical PD, and borderline dominant age-related TDP-43 encephalopathy [181]. ALS-associated mutations specifically enhanced TDP-43 accumulation not only in the cytoplasm but also in mitochondria [182]. A study showed that pharmacological inhibition or genetic deletion of cGAS and its downstream signaling partner STING blocked TDP-43-induced upregulation of NF-κB and IFN-I in induced pluripotent stem cell (iPSC)-derived motor neurons and TDP-43 mutant mice. The mechanism is related to the fact that TDP-43 causes inflammation by stimulating mitochondrial DNA release, which is subsequently sensed by the cytoplasmic cGAS-STING pathway. In addition, the authors observed elevated levels of the specific cGAS signaling metabolite cGAMP in patient spinal cord samples, which may be a biomarker of mtDNA release and cGAS-STING activation in ALS patients [183]. In addition to TDP-43, the SOD1 mutation is a risk factor associated with ALS, and neuroinflammation, one of the most prominent features of ALS driven by misfolding of SOD1 (SOD1 mutant, SOD1^Mut) common to familial and sporadic patients and rodent models, causes microglia and astrocyte activation, T lymphocyte infiltration, and overproduction of pro-inflammatory cytokines and chemokines that can induce motor neurons death [184]. SOD1^Mut disrupts mitochondria, leading to their dysfunction and the release of mtDNA and mitochondrial RNA:DNA heterodimeric structures into the cytoplasm in an mPTP-independent manner, which activates the cGAS/DEAD-box helicase 41 (DDX41)-STING pathway, inducing the activation of the constitutive basis of IFN-I and ISGs, and eventually exacerbating neuroinflammation and neuronal death [185]. These findings emphasize the importance of the common DNA-sensing pathway between SOD1 and TDP-43 in influencing ALS progression. The cGAS-STING pathway is also regulated by other proteins during the progression of ALS. Listerin suppresses the cGAS-mediated innate immune response by binding to cGAS on endosomes and inducing its K63-linked ubiquitination, a process facilitated by recruiting the E3 ligase tripartite motif-containing 27 (TRIM27). The ubiquitinated cGAS is subsequently targeted by the ESCRT machinery, which directs it to endosomes for degradation. Consequently, overexpression of Listerin effectively reduces neuroinflammation and improves disease progression in ALS mice [186]. Furthermore, reducing egl-9 family hypoxia-inducible factor 2 (Egln2) levels safeguarded motor neurons and alleviated the ALS phenotype across zebrafish models and a mouse model, with the underlying mechanism involving inhibition of STING-mediated IFN-I production [187]. Notably, the functions of the cGAS-STING pathway in ALS are predominantly centered on neuroinflammation, and its other potential roles warrant further exploration.

Huntington’s disease

HD is an inherited neurodegenerative disorder characterized by neuropsychiatric symptoms, movement disorders, and progressive cognitive impairment. Early in the course of the disease, patients may present with asymptomatic or mild psychiatric symptoms, and as the disease progresses, motor deficits, most notably progressive choreiform movements, can develop, along with worsening of the patient’s emotional and cognitive symptoms [188].

HD is a debilitating neurodegenerative genetic disorder caused by a polyglutamine-coding (cytosine-adenine-guanine, CAG) trinucleotide repeat amplification in the huntingtin (mutant huntingtin, mHTT) gene. The widespread expression of mHTT causes significant damage to the striatum and cortex and leads to extensive peripheral defects as the disease progresses.

Over the past 150 years of research history, a large number of hypotheses have been proposed for the pathogenic mechanisms of HD, including excitotoxicity, disruption of protein homeostasis, mitochondrial dysfunction, transcriptional dysregulation, metabolic defects, dopaminergic imbalance, and neuroinflammation [189]. The gradual accumulation of reactive microglia and reactive astrocytes in brain tissue throughout the disease process in HD is evidence of neuroinflammation [190]. A previous study showed that cGAS is a key regulator of inflammatory and autophagic responses in HD. In HD striatal cells, protein levels and activity of cGAS (based on phosphorylated STING and phosphorylated TBK1 levels) as well as expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10), were increased. In contrast, cGAS deletion decreased the expression of inflammatory genes while inhibiting the upregulation of autophagy in HD cells. The authors therefore concluded that cGAS mediates inflammatory and autophagic responses in HD and that targeting the cGAS pathway may provide therapeutic benefit in HD [191]. Currently, little is known about the functions of the cGAS-STING pathway in HD, which merits further investigation.

Stoke

Ischemic stroke is a leading cause of global morbidity and mortality, with thrombolytic therapy and mechanical thrombectomy often failing to restore full functionality, leaving patients with long-term disabilities, cognitive impairments, and imposing significant emotional and financial burdens on their families [192, 193]. The complex pathomechanism of ischemic stroke involves disrupted cerebral blood flow, leading to ATP depletion and nutrient deprivation in affected brain regions. This triggers a cascade of pathophysiological events, including oxidative stress, ER stress (ERS), and neuroinflammatory responses, ultimately resulting in neuronal death and dysfunction [194].

Cerebral ischemia/reperfusion injury (CI/RI) induces excessive ROS, damaged DNA, lipids, and other cellular components. Normally, damaged DNA is degraded by enzymes such as deoxyribonuclease I (DNase I), DNase II, and TREX1 [195]. However, oxidatively damaged DNA accumulates in the cytoplasm due to incomplete degradation, activating the cGAS-STING pathway [196, 197]. Furthermore, ischemic stroke can activate p38MAPK and elevate retinoblastoma protein (Rb) levels by causing an excess of ROS in neurons, and subsequently impair mitochondrial function and promote damaged DNA leakage into the cytoplasm to activate the cGAS signaling [198, 199]. In addition, neuronal cell death after stroke leads to the release of DNA from the nucleus or mitochondria into the extracellular space, where it accumulates in microglia and activates the cGAS-STING signaling pathway, thereby exacerbating neuroinflammation and brain tissue damage [200–204].

Neuroinflammation in ischemic stroke can lead to disruption of immune homeostasis and increased organ damage [205]. In normal brain physiology, microglia play an important role in phagocytosis of cellular debris and synthesis of anti-inflammatory cytokines and growth factors. However, in the infarcted area of the brain, activated microglia can secrete a large number of pro-inflammatory cytokines and cytotoxic drugs, such as tumor necrosis factor-alpha (TNF-α), IL-1β, and interleukin 6 (IL-6), which lead to further neuronal death and aggravate the brain damage after stroke [206, 207]. cGAS enzymes are predominantly distributed in microglia within the brain and directly contribute to the immune response in the CNS [208]. It has been shown that loss of cGAS function inhibits pathological remodeling and promotes angiogenesis and early survival, which correlates with the fact that cGAS can promote the transition of macrophages to a reparative phenotype. Whereas microglia are highly specialized macrophages, their M1/M2 polarization is also regulated by the cGAS-STING pathway. cGAS-STING promotes microglia polarization toward the M1 phenotype and inhibits microglia polarization in M2 by modulating IRF3 and NF-κB in ischemic stroke, thereby causing neuroinflammation and cognitive function [201–203, 209]. Therefore, the cGAS-STING pathway-mediated microglial polarization may represent a novel mechanism for inducing neuroinflammation, and targeting the cGAS-STING pathway may offer a promising avenue for immunotherapy in the treatment of ischemic stroke.

A recent study showed that the cGAS-STING pathway can activate excessive autophagy in the brain in ischemic stroke. In contrast, activin A can inhibit this autophagy via the phosphatidylinositol 3-kinase/protein kinase B pathway (PI3K/PKB), thereby improving neurologic function and reducing infarct size [210]. In addition to autophagic modulation, the cGAS-STING pathway may be implicated in ferroptosis. Iron can participate in free radical-producing reactions that lead to lipid peroxidation, mitochondrial DNA damage, and increased brain sensitivity to ischemia and hypoxia [211, 212]. Ferritin is the major storage form of iron and is regulated by nuclear receptor coactivator 4 (NCOA4) [213]. Increased NCOA4 expression leads to substantial degradation of ferritin, resulting in increased free iron and ferroptosis, whereas inhibition of the cGAS-STING pathway abrogated this phenomenon [214, 215]. Unfortunately, the mechanism by which the cGAS-STING pathway regulates ferroptosis remains largely unknown. Nevertheless, recent studies have shown that cGAS is a promising therapeutic target in attenuating stroke-related neurological damage. Blocking cGAS-STING signaling through pharmacological or genetic approaches can affect oxidative stress, autophagy, ferroptosis, and apoptosis, thereby improving the functional outcome of stroke [200, 201, 216].

The applications of cGAS-STING inhibitors

The cGAS-STING signaling pathway has emerged as a promising therapeutic target for mitigating neuroinflammation and neurological disorders. Study using cellular and animal models have demonstrated that pharmacological inhibition of the cGAS-STING pathway can effectively ameliorate pathological features of NDs [217]. Consequently, the development of selective small-molecule inhibitors against this pathway offers considerable therapeutic potential. In this section, we outline recently identified cGAS and STING antagonists and summarize their proposed mechanisms of action.

cGAS inhibitors

As an initiator of the cGAS-STING signaling pathway, inhibition of cGAS activity prevents activation of the downstream pathway and may play a role in the treatment of NDs [217]. A lot of literature has been presented on the design of structure-based cGAS inhibitors [218–222]. cGAS antagonists compete with ATP or GTP substrates or the product cGAMP. Other major cGAS antagonists can compete with DNA for binding to cGAS, thereby interfering with the initial activation step of cGAS [223–227] (Table 1).

Table 1.

Structures and applications of cGAS inhibitors

Names	Structures	Mechanisms	Biological effects	Applications	Penetrates the BBB	References
PF-06928125		Inhibits the catalytic activity	Lack of inhibitory activity in the cell assay	-	Unknown	[219]
RU0.521		Inhibits the catalytic activity	Inhibits cGAS activity in BMDM cells and reduces the expression level of IFN-β	Improves aging-related endothelial dysfunctions	Unknown	[133, 228]
G150		Inhibits the catalytic activity	Inhibits the cGAS-STING signaling pathway	Combining with melatonin inhibits macrophage aging	Unknown	[220, 229, 230]
Compound S3		Inhibits the catalytic activity	Binds to cGAS through hydrogen bonding with R376 and N482	-	Unknown	[222]
Quinacrine		Blocks cGAS-dsDNA interaction	Reduces the expression of IFN-β and IL-1β in THP1 cells	Used for the prevention and treatment of malaria	Yes	[223–225]
Suramin		Blocks cGAS-dsDNA interaction	Reduces the expression of IFN-I in THP-1 cells	Acts as anti- trypanosomiasis, anti-tumor, antiviral, and immunomodulatory agents	No	[227]
A151	-	Competitively binds to the DNA-binding domain of cGAS	Inhibits IFN-I response in TREX1-deficient cells	-	Unknown	[226]
Aspirin		Acetylation of cGAS	Acetylate lysine sites in the DNA binding domain, catalytic active domain, and dimerization domain	Inhibit the cGAS-mediated autoimmune response in AGS mouse models	Yes	[105, 231]
CU-76		Inhibits the dimerization of cGAS	Inhibits IRF3 activation in THP-1 cells	-	Unknown	[221]
VENT-03	-	Targeting the cGAS enzyme	Suppress overactive inflammation in autoimmune diseases	SLE	Unknown	[232]

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Catalytic site inhibitors

(1) PF-06928215

PF-06928215, a compound that has been biochemically analyzed to bind to the active site of cGAS, a region typically occupied by adenosine bases of ATP or cGAMP. However, PF-06928215 lacked inhibitory activity in cellular assays. It may be associated with excessive levels of ATP and GTP in cells [219].

(2) RU0.521

RU0.521 is capable of occupying the active site of cGAS and reducing its affinity for ATP without affecting the dsDNA binding [218]. Currently, RU0.521 has a wide range of applications, including amelioration of neuroinflammation caused by subarachnoid hemorrhage and aging-related endothelial dysfunction [133, 228]. The inhibitory effect of RU0.521 on cGAS is selective and is shown to reduce the level of interferon beta 1 (IFNB1) mRNA expression in bone marrow-derived macrophages in TREX1^-/- mice [30, 218]. In the sevoflurane-induced cognitive dysfunction animal model, the cGAS-STING pathway in microglia is significantly activated, whereas RU0.521 pretreatment significantly inhibited sevoflurane-induced activation of NLRP3 inflammasome [233]. Moreover, Intrapool injection of RU0.521 into the brain pool of a hypertensive model showed reductions in microglia polarization, neuroinflammation, sympathetic excitability, and blood pressure [234].

(3) G150

G150 is a pyridoindole-centered compound that could bind to the cGAS active site and inhibit cGAS activity in THP-1 cells and human macrophages [220]. G150 markedly suppressed the paraquat-induced activation of the cGAS-STING pathway in monocytes and reduced transforming growth factor-beta1 (TGF-β1) expression, leading to the inhibition of fibroblast activation [229]. Furthermore, it was combined with melatonin, which could effectively inhibit macrophage aging [230].

(4) Compound S3

Compound S3 was identified as a human cGAS inhibitor using a virtual screening approach; however, its applications remain unknown [222].

Inhibitors that disrupt DNA binding

(1) Antimalarial drugs

Malaria drugs, such as hydroxychloroquine and quinine, inhibit IFN-β production by selectively blocking cGAS-dsDNA interactions, which could be potential treatments for systemic lupus erythematosus (SLE) [223–225].

(2) Suramin

Suramin inhibits cGAS enzyme activity by binding at the dsDNA binding site, thereby disrupting the formation of the cGAS-dsDNA complex. The addition of Suramin to THP-1 cells reduced the levels of IFN-β mRNA and protein [227].

(3) Suppressive oligodeoxynucleotides

A151 can act as a competitive inhibitor of cGAS by interacting with the dsDNA binding domain. A151 inhibits IFN-I production in TREX1-deficient cells and can be used to treat dsDNA-mediated autoimmune diseases [226].

Acetylation of cGAS

Aspirin is a nonsteroidal anti-inflammatory drug that can acetylate lysine sites of cGAS in the DNA binding domain, catalytic active domain, and dimerization domain [231]. Acetylation of cGAS at these sites can prevent its activation and subsequent immune response. A previous study has shown that aspirin can inhibit the cGAS-mediated autoimmune response in Aicardi-Goutières syndrome (AGS) mouse models [105]. Aspirin has a well-established safety profile from long-term clinical use, and the dose required to inhibit the cGAS pathway is well below its conventional therapeutic ceiling, further supporting its potential as a good cGAS inhibitor [235, 236].

Compound with undetermined mechanisms

(1) CU-76

CU-76 is a powerful inhibitor of cGAS; however, obtaining a crystal structure of CU-76 in complex with cGAS has not been feasible, leaving its inhibitory mechanism uncertain [221].

(2) VENT-03

VENT-03, discovered by biotechnology company Ventus Therapeutics, is a potent, selective, and orally administered cGAS inhibitor. It is also the first cGAS inhibitor to be tested in humans. Ventus Therapeutics is developing VENT-03 to target the cGAS enzyme and curb overactive inflammation in autoimmune diseases. In its first-in-human Phase I trial, VENT-03 demonstrated favorable safety and tolerability across all doses tested [237]. Currently, researchers plan to conduct follow-up trials on two complex and challenging autoimmune diseases, systemic lupus erythematosus and systemic sclerosis. In recent clinical studies, VENT-03 is safe and well tolerated in healthy volunteers, exhibiting good pharmacokinetic characteristics [232].

STING inhibitors

As a convergence site of DNA sensors, STING can further transmit downstream activation signals. There are currently two methods to identify STING inhibitors. The first is a molecule that occupies the CDN binding site. The second binds to cysteines (Cys88 or Cys91) residues near the transmembrane structural domain of the STING protein [30] (Table 2).

Table 2.

Structures and applications of STING inhibitors

Names	Structures	Mechanisms	Biological effects	Applications	Penetrates the BBB	References
Compound 18		Competes with CDN	Attaching to STING by forming a 2:1 binding interaction with the open conformation	-	Unknown	[238]
Astin C		Competes with CDN	Preventing the binding of STING and IRF3	Anti-cancer and anti-inflammation	Unknown	[239, 240]
SN-011		Competes with CDN	Interacts with STING residues Tyr167, Leu212, Ser243, Tyr245, and Glu260 to occupy binding pockets and form spatial blockages	Improves the survival rate of acute kidney injury and alleviates renal dysfunction	Unknown	[241]
C-176		Inhibits the palmitoylation	-	Inhibit STING-mediated inflammation-triggered ischemic stroke	Unknown	[242, 243]
C-178		Inhibits the palmitoylation	Inhibits IFN-stimulated gene expression	Inhibits IFN-stimulated gene expression in the AGS mouse model	Unknown	[242]
H-151		Inhibits the palmitoylation	Covalently binds with the Cys91 site of STING to prevent palmitoylation of STING	Improves myocardial cell hypertrophy and alleviates fibrosis of infarcted myocardial tissue	Yes	[242]
Nitro fatty acids		Inhibits the palmitoylation	Reduces the production of IFN-I	Reduces fat accumulation caused by a high-fat diet	Unknown	[244]
ISD017	-	Blocks the essential trafficking of STING	Reducing the production of inflammatory cytokines and IFN-I	Reduce the severity of glomerulonephritis in 129.B6.Fcgr2b-deficient mice and increase the long-term survival rate	Unknown	[245, 246]
Compound 13		The exact mechanism remains unelucidated	-	-	Unknown	[30, 231, 247]

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STING antagonists targeting the CDN-binding site

(1) Compound 18

Compound 18 can displace cGAMP and stabilize the “open” conformation of STING. A central assumption is that maintaining this conformation will block all downstream signaling mediated by STING. And further study showed that Compound 18 could inhibit cGAMP-induced IFN-β secretion in THP-1 cells [238].

(2) Astin C

The cyclic peptide Astin C can competitively bind to the CDN site and block the recruitment of IRF3 to the STING signalosome, thereby preventing cGAS-STING downstream signaling and inhibiting the intrinsic inflammatory response triggered by cytoplasmic DNA [239, 240].

(3) SN-011

SN-011 is a potent STING inhibitor with greater affinity for the CDN of STING than endogenous 2‘3’-cGAMP, while locking the STING dimer in an open, inactive conformation and inhibiting the expression of interferons and inflammatory cytokines [241].

Targeting STING palmitoylation sites

(1) Nitrofurans (C-176 and C-178)

C-176 and C-178 covalently bind to the predicted transmembrane cysteine residue 91 of STING, preventing activation-induced palmitoylation. Administration of C-176 in mice markedly decreased the rise in serum IFN-I and IL-6 levels triggered by STING agonists and alleviated symptoms of autoinflammatory disease. C-178, which functions in a manner comparable to C-176, exhibits similar inhibitory effects [242]. Further, a study showed that C-176 can inhibit the phosphorylation of STING, enhance hippocampal neurocognitive function, and improve the prognosis of PD [203]. Recently, A new nanomedicine has been developed that synergistically combines the DNAzyme epitope of the cerium (Ce⁴⁺) enzyme with C-176, thereby enhancing the therapeutic efficacy for stroke treatment [243].

(2) H-151

H-151 is a covalent STING inhibitor that blocks STING palmitoylation and subsequent interaction with TBK1, which is essential for STING signaling. In various cellular assays, H-151 inhibited TBK1 phosphorylation and STING Cys91 palmitoylation by decreasing IFN-I responses [242]. H-151 has a similar mechanism to C176 and has been found to reduce neuroinflammation and pathological protein deposition in ALS and AD mice [151, 183, 218]. Of note, H-151 effectively inhibited the expression of ISGs and pro-inflammatory genes, significantly improving physiological and cognitive functions in naturally aging mice. Not only that, STING inhibitor H-151 also promotes a healthy CNS, reduces the immune response of microglia and astrocytes, prevents the loss of hippocampal neurons and enhances synaptic activity, which shows good prospects for application [5].

(3) Nitro fatty acids

Nitro fatty acids (NO₂-FA) are endogenous substances produced during viral infections by the addition of nitrogen dioxide (NO₂) to unsaturated fatty acids. The endogenous NO₂-FA, such as nitro linoleic acid (NO₂-cLA) and nitro oleic acid (NO₂-OA), was covalently modified with STING on the nitro olefins of the fatty acids by Michael addition, thereby inhibiting STING palmitoylation and IFN-I production [244].

Blocking the trafficking of STING

ISD017 is a unique STING transport inhibitor that prevents the transport of STING from the endoplasmic reticulum to the Golgi apparatus, thereby reducing the production of inflammatory cytokines and IFN-I. According to Prabakaran et al.‘s research, ISD017 specifically inhibits all downstream functions of STING currently known, such as IFN-I, inflammatory cytokines, autophagy, and apoptosis [245]. The monomer form of ISD017 demonstrates a more pronounced inhibitory effect, with potency comparable to that of the covalent inhibitor H-151 [234]. In addition, studies have shown that ISD017 treatment can alleviate the severity of glomerulonephritis in 129.B6.Fcgr2b-deficient mice and increase long-term survival rates [246].

Inhibitor of unknown mechanism

Compound 13 was identified as a hit from a cGAS-STING pathway-targeted, cell-based phenotypic chemical screen of approximately 250,000 compounds. Treatment of THP-1 cells with compound 13 significantly reduced the expression of Cxcl10 mRNA, a key marker of ISG activity, following dsDNA stimulation, suggesting a dampened interferon response. However, the precise mechanism of action of compound 13 remains to be elucidated [247].

Clinical trial status of cGAS/STING inhibitors

The cGAS-STING signaling transduction has been identified as a key pathway in inflammatory diseases, including cancer, autoimmune diseases, and NDs [248]. Recent studies have revealed the existence and functional significance of cGAS-STING signaling in various cell types of the CNS, including resident brain immune cells, neurons, and glial cells. Neuroinflammation is the activation of the brain’s inflammatory response, characterized by the expression of ISG, pro-inflammatory cytokines, chemokines, ROS, and the production of second messengers [249]. Persistent pathological neuropathy can lead to various harmful effects, including peripheral immune cell infiltration, increased and disrupted blood-brain barrier (BBB) permeability, demyelination, synaptic loss, and neuronal death. As neuroinflammation has been shown to play a critical role in NDs, there is an increasing amount of research on the role of the cGAS-STING pathway in the CNS [49, 250]. Multiple small-molecule inhibitors targeting the cGAS-STING axis have been developed and applied for the treatment of neuroinflammation, laying the foundation for the development of targeted drugs [251]. However, currently, except for VENT-03, which has undergone a phase I clinical trial, no cGAS-STING inhibitors targeting the treatment of neurodegenerative diseases or other indications have entered the clinical trial stage. Therefore, the detailed knowledge of the pharmacokinetic properties of cGAS-STING inhibitors in the human brain is still limited [252].

Challenges in the development of cGAS/STING inhibitors

Currently, the research and development of cGAS inhibitors mainly focus on targeting catalytic sites and DNA binding sites. Some studies suggest that when designing catalytic site inhibitors, attention should be paid to their competitive binding with substrates AMP, GMP, and product 2‘,3’-cGAMP, and overcoming the high affinity of substrates also poses new challenges for researchers. In terms of STING inhibitors, inhibitors targeting CDN binding sites need to overcome large binding pockets in compound screening and rational design [235]. Secondly, long-term inhibition of the cGAS-STING pathway may increase susceptibility to infection and cancer [253]. To date, although cGAS or STING-deficient mice have not reported spontaneous infection or increased incidence rate of cancer, consideration should be given to the absence of specific pathogen environments and the differences in susceptibility to cancer between mice and humans [254]. Thirdly, a large amount of evidence suggests that the cGAS-STING pathway plays an important role in mouse disease models, and an increasing amount of data suggests that this pathway is also active in various human diseases. However, there are species-specific differences between mouse and human cGAS and STING proteins, such as activation of cGAS-STING signaling after exogenous pathogen infection, and phosphorylation of STING at Ser366 in humans and Ser365 in mice when STING is transferred to the Golgi apparatus to recruit TBK1 [255]. Due to the structural differences between human-derived STING (hSTING) and mouse-derived STING (mSTING), the results of animal models cannot fully correspond to humans. Such species-specific differences require more clinical models to evaluate the effectiveness of inhibitors [235, 256]. Fourthly, the BBB permeability and off-target effects are important obstacles to clinical translation of cGAS-STING inhibitors. Therefore, it is particularly important to develop brain penetrant molecules that can effectively regulate pathways within the CNS without producing off-target effects [257]. Employing the bionic nanotechnology systems and intelligent hydrogels may be good choices [258–260]. For example, the cerium-based nanoparticles developed for research can be loaded with STING inhibitor C-176, which synergistically reduces neuroinflammation and protects neurons in ischemic injury models by effectively inhibiting the cGAS-STING pathway [243, 261]. However, the safety, stability, and long-term effects of nanocarriers are still unknown and will be the direction of future research [251]. Although the number of cGAS-STING inhibitors in clinical research remains limited, the significant progress in this field and the safety profile indicated by cGAS-STING loss-of-function models strongly support the broad therapeutic potential of cGAS inhibitors for various neurological diseases.

Conclusions and perspectives

The past few years have seen an explosion of interest in and knowledge about the cGAS-STING pathway in aging and neurodegenerative disease. Although this pathway is indispensable for host defense and is tightly regulated under physiological conditions, its aberrant activation emerges as a potent driver of the neuroinflammatory cascade and neuronal dysfunction during aging. The accumulation of both exogenous and endogenous DNA serves as a persistent trigger for cGAS, culminating in a vicious cycle of STING-dependent IFN-I and pro-inflammatory cytokine production. This chronic, low-grade inflammation is a hallmark of aged brain tissue and a key contributor to the progression of conditions like AD, PD, and ALS. The promising results from preclinical studies utilizing cGAS or STING inhibitors, which have demonstrated efficacy in ameliorating cognitive decline and neuropathology in various models, underscore the therapeutic potential of targeting this pathway. However, several pivotal questions and challenges must be addressed to translate these foundational discoveries into effective clinical interventions.

Sources of DNA triggers and their relative contributions: The characteristics of the DNA that activate the cGAS-STING pathway are crucial. The origins, oxidation extent, amount, manner, and rate of DNA release (e.g., during different forms of cell death) significantly influence the intensity of the downstream immune response. The relative contribution of mtDNA versus nuclear DNA and viral DNA remains hotly debated. Research has shown that mtDNA acts as an important cGAS-STING driver; it can be transferred into the nuclear genome and contribute to genomic instability. Additionally, oxidized mtDNA induces significantly higher levels of interferon (IFN-α/IFN-β) mRNA and leads to more severe tissue injury than non-oxidized mtDNA. So the characteristics of DNA might have a potential effect on the intensity of cGAS-STING pathway activation.

Degree of cGAS-STING activation and disease outcomes: The degree of STING activation is a critical determinant in whether the pathway leads to protective or detrimental disease outcomes. Low or moderate, or specifically targeted activation of the cGAS-STING pathway can exert protective effects, as demonstrated by the alleviation of inflammation and fibrosis in a chronic pancreatitis model through STING activation in Th17 cells. In contrast, strong or excessive STING activation can lead to a life-threatening cytokine storm. These findings suggest the existence of a therapeutic window for modulating the cGAS-STING pathway, where an appropriate level of activation may elicit beneficial effects without inducing harmful immunotoxicity.

Cell-type specificity: The cellular context of STING activation is paramount. The same signal in different immune cells can drive opposing disease pathways. cGAS-STING activation in innate immune cells is consistently associated with driving inflammation, while cGAS-STING activation in adaptive immune cells can have an anti-inflammatory effect. For neurodegenerative disease, the neuroinflammatory response in the brain is highly complex, involving microglia, astrocytes, oligodendrocytes, and even neurons themselves. It remains unclear which specific cell type(s) are the most destructive when activated, if microglial activation primarily drives pathology, or if astrocytic or neuronal responses play an equally important role remain unclear. The disease outcome is not just a function of whether cGAS-STING is activated, but where it is activated, which will be crucial for clinical trial design and therapeutic development.

Therapeutic development and safety considerations: Therapeutic development presents significant challenges in targeting the cGAS-STING pathway. A major hurdle stems from structural differences in STING proteins between experimental animals and humans, which complicates the translational potential of preclinical findings. For instance, agonists like 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which are potent activators of mouse STING, fail to effectively activate human STING due to these species-specific variations, thereby limiting their clinical applicability. The crucial physiological functions of the cGAS-STING pathway underscore the safety concerns associated with its long-term systemic inhibition. Although the global STING knockout mice show improvements in spatial learning and memory, they simultaneously exhibit increased susceptibility to viral infections, diminished antitumor immune responses, and disruptions in glucose homeostasis. Given the fundamental role of cGAS-STING in innate immunity, systemic long-term inhibition could carry a significant risk of increased susceptibility to infections, impaired glucose metabolism, or cancer immunosurveillance. Therefore, developing refined therapeutic strategies that can achieve cell-type-specific silencing or temporal modulation of STING signaling without broadly crippling innate immunity is paramount for harnessing the therapeutic potential of STING modulation while minimizing adverse effects.

In conclusion, the cGAS-STING pathway serves as a master regulator of age-related neuroinflammation and a compelling therapeutic target for a range of NDs. Importantly, the pathological outcome is determined not merely by whether the pathway is activated, but more profoundly by the strength of the signal, the cellular context of activation, and the source and properties of the stimulating DNA, such as whether it is exogenous or endogenous, oxidized, or otherwise modified. Given this complexity, a precise understanding of the cGAS-STING pathway is essential to understanding neuroinflammatory damage. Looking ahead, we should aim to design therapeutic strategies that precisely modulate the cGAS-STING pathway-both in degree of activity and cell-type specificity-to safely unlock its potential for clinical benefit.

Acknowledgements

None.

Abbreviations

AARS: alanyl-tRNA synthetases
AD: Alzheimer’s disease
AGS: Aicardi-Goutières syndrome
ALS: Amyotrophic lateral sclerosis
AMD: Age-related macular degeneration
AP: acidic patch
ATM: ataxia-telangiectasia mutated
ATP: adenosine-5’-triphosphate
AURKB: aurora kinase B
Aβ: amyloid-β
BAF: barrier-to-autointegration factor
BBB: blood-brain barrier
BER: base excision repair
C3R: complement 3 receptor
C9orf72: ORF 72 on chromosome 9
CAG: cytosine-adenine-guanine
CDK1: cyclin-dependent kinase 1
CDN: cyclic dinucleotide
Ce⁴⁺: cerium
cGAMP: Cyclic GMP-AMP
cGAS: Cyclic GMP-AMP synthase
CI/RI: Cerebral ischemia/reperfusion injury
CNS: central nervous system
CNV: choroidal neovascularization
CTD: carboxyl-terminal domain
CTT: C-terminal tail
DAM: disease-associated microglial
DAMPs: damage-associated molecular patterns
DDX41: DEAD-box helicase 41
DMXAA: 5,6-dimethylxanthenone-4-acetic acid
DNase I: deoxyribonuclease I
DNase II: deoxyribonuclease II
Drp1: dynamin related protein 1
dsDNA: double-stranded DNA
DUBs: deubiquitinating enzymes
Egln2: egl-9 family hypoxia-inducible factor 2
eNOS: endothelial nitric oxide synthase
ER: endoplasmic reticulum
ERGIC: ER-Golgi intermediate compartment
ERS: ER stress
ESCRT: endosomal sorting complexes required for transport
FUS: fused in sarcoma
GABARAP: GABA type A receptor-associated protein
GTP: guanosine triphosphate
hcGAS: Human cGAS
HCQ: hydroxychloroquine
HD: Huntington’s disease
hSTING: human-derived STING
IDR: intrinsically disordered region
IFNAR1: interferon alpha receptor 1
IFNB1: interferon beta 1
IFN-I: Type I interferon
IL-6: interleukin 6
IMM: mitochondrial matrix by the inner
INOS: inducible nitric oxide synthase
iPSC: induced pluripotent stem cell
IRF3: interferon regulatory factor 3
IRF7: interferon regulatory factor 7
IRF9: interferon regulatory factor 9
ISG: interferon-stimulated gene
ISGF3: interferon-stimulated gene factor 3
ISRE: interferon-stimulated response element
JAK1: Janus kinas 1
KAT5: lysine acetyltransferase 5
LBD: ligand-binding structural domain
LCN2: Lipocalin-2
LLPS: liquid-liquid phase separation
LRRK2: leucine-rich repeat kinase 2
MAMPs: metabolism-associated molecular patterns
MAMs: mitochondrial-associated membranes
MDVs: mitochondrial-derived vesicles
MEF2C: myocyte enhancer factor 2c
MFN1: mitofusin-1
MFN2: mitofusin-2
mHTT: mutant huntingtin
MLOs: membrane-less organelles
Mn²⁺: manganese ions
MNi: micronuclei
mPTP: mitochondrial permeability transition pore
MRN: Mre11-Rad50-NBS1
mROS: mitochondrial reactive oxygen species
mSTING: mouse-derived STING
mtDNA: mitochondrial DNA
MTS: mitochondrial targeting signal
NCOA4: nuclear receptor coactivator 4
NDs: Neurodegenerative diseases
NE: nuclear envelope
NFTs: neurofibrillary tangles
NLR: nucleotide-binding and oligomerization domain like receptor
NLRP3: nucleotide-binding and oligomerization domain like receptor family pyrin domain-containing 3
NLS: nuclear localization signals
NM: nuclear membrane
NO: nitric oxide
NO₂: nitrogen dioxide
NO₂-cLA: nitro linoleic acid
NO₂-FA: Nitro fatty acids
NO₂-OA: nitro oleic acid
NOD: nucleotide-binding and oligomerization domain
NPC: nuclear pore complex
NPCs: nuclear pore complexes
OMM: mitochondrial matrix by the outer
OPA1: optic atrophy 1
OPTN: optineurin
PAMPs: pathogen-associated molecular patterns
PCBP1: poly r(C) binding protein 1
PD: Parkinson’s disease
PFF: preformed fibrils
PI(4,5)P₂: phosphatidylinositol 4,5-bisphosphate
PI3K/PKB: phosphatidylinositol 3-kinase/protein kinase B pathway
PINK1: putative kinase protein 1
POLG: polymerase gamma
POLγ: Polymerase γ
PP1: protein phosphatase 1
PPS: protein phase separation
PRMT5: protein arginine methyltransferase 5
PRRs: pattern recognition receptors
PTEN: Phosphatase and tensin homolog
PTMs: post-translational modifications
RIG-I: retinoic acid-inducible gene I
RLRs: retinoic acid-inducible gene I like receptors
ROS: reactive oxygen species
RPE: retinal pigment epithelial
SAM50: sorting and assembly machinery 50
SASP: senescence-associated secretory phenotype
SLE: systemic lupus erythematosus
SOD1: Superoxide dismutase 1
SOD1^Mut: SOD1 mutant
SSBP1: ssDNA-binding protein
ssDNA: single-stranded DNA
STAT1: signal transducer and activator of transcription 1
STING: stimulator of interferon genes
SUV39H1: suppressor of variegation 3–9 homolog 1
TBK1: TANK-binding kinase 1
TDP-43: TAR DNA-binding protein 43
TFAM: Mitochondrial transcription factor A
TGF-β1: transforming growth factor-beta1
TNF-α: tumor necrosis factor-alpha
TREX1: three prime repair exonuclease 1
TRIM27: tripartite motif-containing 27
TRIM56: tripartite motif protein 56
TWINKLE: two novel mutations in PEO1
UHRF1: ubiquitin-like with PHD and ring finger domains 1
USP15: ubiquitin-specific protease 15
VDAC: voltage-dependent anion channel
YY1: Yin Yang 1
Zn²⁺: Zinc ions
ZYG11B: ZYG-11 family member B
α-syn: α-synuclein

Author contributions

Zheng Wu: Investigation, Writing-original draft. Rong-Jun Jia: Writing-original draft. Qi Zhang: Visualization, Writing-original draft. Li-Yan Huang: Methodology, Resources. Jun-Ting Yan: Investigation, Resources. Yan-Hui Zhang: Conceptualization, Writing-review and editing. Yong-Gang Fan: Conceptualization, Writing-review and editing.

Funding

This work was supported by the National Natural Science Foundation of China (82301626).

Data availability

No data was used for the research described in the article.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Zheng Wu, Rong-Jun Jia and Qi Zhang contributed equally to this work.

Contributor Information

Yan-Hui Zhang, Email: zhangyanhui@cmu.edu.cn.

Yong-Gang Fan, Email: fanyonggang@muhn.edu.cn.

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Data Availability Statement

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PERMALINK

The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration

Zheng Wu

Rong-Jun Jia

Qi Zhang

Li-Yan Huang

Jun-Ting Yan

Yan-Hui Zhang

Yong-Gang Fan

Abstract

Abstract

Graphical Abstract

Introduction

The characteristics of the cGAS-STING pathway

cGAS

Fig. 1.

Fig. 2.

STING

Fig. 3.

Regulatory networks of the cGAS-STING pathway

Exogenous viral DNA-mediated activation of the cGAS-STING pathway

mtDNA-mediated activation of the cGAS-STING pathway

Fig. 4.

Nuclear DNA-mediated activation of the cGAS-STING pathway

Fig. 5.

Fig. 6.

Protein separation regulates the cGAS-STING pathway

Fig. 7.

The effect of post-translational modifications on cGAS

Phosphorylation

Acetylation

Methylation

Ubiquitination

SUMOylation

Lactylation

Roles and mechanisms of cGAS-STING in aging

Abnormal DNA accumulation during aging mediates the activation of the cGAS-STING pathway

cGAS-STING pathway activation exacerbates the aging and aging-related diseases

Roles and mechanisms of cGAS-STING in NDs

Alzheimer’s disease

Fig. 8.

Parkinson’s disease

Fig. 9.

Amyotrophic lateral sclerosis

Huntington’s disease

Stoke

The applications of cGAS-STING inhibitors

cGAS inhibitors

Table 1.

Catalytic site inhibitors

Inhibitors that disrupt DNA binding

Acetylation of cGAS

Compound with undetermined mechanisms

STING inhibitors

Table 2.

STING antagonists targeting the CDN-binding site

Targeting STING palmitoylation sites

Blocking the trafficking of STING

Inhibitor of unknown mechanism

Clinical trial status of cGAS/STING inhibitors

Challenges in the development of cGAS/STING inhibitors

Conclusions and perspectives

Acknowledgements

Abbreviations

Author contributions

Funding

Data availability

Declarations

Ethical approval and consent to participate

Consent for publication

Competing interests

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

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