Parkinson's disease (PD), recognized as the second most common neurodegenerative disorder following Alzheimer's disease, has exhibited a steadily increasing global prevalence, resulting in significant socioeconomic burdens for affected individuals, caregivers, and healthcare systems (Ben-Shlomo et al., 2024; Tolosa et al., 2021). The cardinal motor features of PD encompass resting tremor, rigidity, bradykinesia, and postural instability (Morris et al., 2024). Emerging evidence highlights the growing clinical relevance of non-motor manifestations in PD, with cognitive dysfunction representing a critical research area (Wallace et al., 2022). Longitudinal studies indicate that nearly 25 % of newly diagnosed PD patients demonstrate mild cognitive impairment (MCI) at initial presentation, while the cumulative incidence of dementia approaches 83 % after two decades of disease duration (Aarsland et al., 2021; Jellinger, 2023). Nevertheless, the pathophysiological mechanisms underlying mild cognitive decline in PD remain poorly elucidated (Aarsland et al., 2021). Elucidating these mechanisms during the early disease course may enable timely biomarker identification and targeted therapeutic strategies, ultimately modifying the trajectory of neurodegeneration (Jellinger, 2023).

Microglia are the innate immune sentinels residing in the central nervous system (CNS) that dynamically survey parenchymal microenvironments through process motility, maintaining neural homeostasis by rapidly responding to neuropathological insults (Fumagalli et al., 2025; Walsh and Lukens, 2025). Paradoxically, while this surveillance mechanism serves neuroprotective functions, sustained microglial hyperactivation triggers excessive synaptic phagocytosis and maladaptive pruning, processes strongly associated with cognitive deterioration in neurodegenerative disorders (Augusto-Oliveira et al., 2025; Hong et al., 2016; Zhang et al., 2021). Notably, accumulating evidence demonstrates that pathogenic α-synuclein (α-Syn) fibrils propagate microglial reactivity within limbic-cortical circuits, particularly affecting the hippocampus-prefrontal network in PD pathogenesis(Wang et al., 2023b). Nevertheless, the spatiotemporal dynamics of α-Syn-mediated microglial priming and subsequent synaptic stripping remain mechanistically undefined. Emerging research implicates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis as a critical mediator of innate immune activation (Chen and Xu, 2023). Specifically, cytosolic cGAS detects double-stranded DNA fragments to catalyze 2′,3′-cyclic GMP-AMP (cGAMP) synthesis, which functions as a second messenger to engage STING signaling. This molecular cascade culminates in the transcriptional upregulation of type I interferons (IFN-α/β) and interleukin-1β (IL-1β), establishing a pro-inflammatory milieu that perpetuates neurodegenerative cascades.

The STING pathway plays a pivotal role in neurodegenerative diseases. Postmortem analyses of human neurodegenerative specimens have revealed aberrant activation of the cGAS-STING axis in both endothelial cells and neurons(Ferecsko et al., 2023; Quan et al., 2025). In aged murine hippocampal tissues, cGAS-STING pathway activation drives microglial reactivity and neurodegenerative pathology (Gulen et al., 2023). Pharmacological inhibition of this pathway reduces microglial accumulation, mitigates neuroinflammatory responses in senescent brains, and preserves neuronal integrity by restoring synaptic plasticity (Huang et al., 2023). Furthermore, preclinical PD models demonstrate analogous cGAS-STING hyperactivation, while STING knockout substantially attenuates neurodegenerative pathology by dampening neuroinflammation. Collectively, these findings position pharmacological targeting of STING signaling as a promising therapeutic strategy to disrupt the neuroinflammatory cascade and modify disease progression in neurodegeneration.

O-linked β-N-acetylglucosamine (O-GlcNAc) modification represents an evolutionarily conserved posttranslational modification system that dynamically interfaces cellular metabolism with epigenetic regulation (Chatham et al., 2021; Li et al., 2019). This unique monosaccharide modification, occurring predominantly on nuclear and cytoplasmic proteins, exhibits rapid cycling between its glycosylated and unmodified states—a process governed by the opposing enzymatic activities of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) (Ye et al., 2023). Mechanistically, OGT utilizes uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end-product of the hexosamine biosynthetic pathway (HBP), to catalyze stereospecific O-GlcNAc conjugation to serine/threonine residues, while OGA enzymatically dismantles these modifications via β-N-acetylglucosaminidase activity, establishing a nutrient-responsive rheostat for cellular signaling. Intriguingly, recent advances in glycoproteomics have unmasked STING as a novel O-GlcNAcylated protein within the cGAS-STING-IFN axis, with site-specific mapping identifying conserved modification sites in its cytoplasmic domain (Li et al., 2024). The functional pleiotropy of this glycosylation event—particularly its capacity to allosterically modulate STING conformation, subcellular trafficking, or interaction with downstream effectors-may constitute an unrecognized molecular checkpoint in PD pathogenesis (Hinkle et al., 2022). Elucidating whether O-GlcNAc-STING crosstalk exerts neuroprotective effects through mitigating α-synuclein proteotoxicity or suppressing neuroinflammatory microglial activation represents a critical knowledge gap with therapeutic implications.

Thiamet G (TMG) is a potent O-GlcNAcase (OGA) inhibitor and it can augment intracellular O-GlcNAc levels through selective inhibition of OGA-mediated protein deglycosylation. It has been reported that TMG exerted protective effects in PD neuropathology by blunting the cellular uptake of α-syn fibrils and thereby inhibiting α-syn spread among the neurons (Tavassoly et al., 2021). Emerging evidence demonstrates that TMG administration effectively mitigates cognitive impairments associated with rapid eye movement sleep deprivation (REMSD) (Kim et al., 2021). Notably, preclinical studies reveal TMG's dual neuroprotective mechanisms: attenuating neuroinflammation via suppression of microglial hyperactivation in middle cerebral artery occlusion (MCAO) models (He et al., 2017), while concurrently modulating critical signaling pathways including NF-κB phosphorylation and gasdermin D (GSDMD)-mediated pyroptosis in microglia (Yu et al., 2024). However, it remains unclear whether TMG's anti-inflammatory efficacy extends to Parkinson's disease (PD)-associated cognitive decline, particularly regarding its interaction with the STING pathway in microglial immunomodulation. This investigation systematically evaluates TMG's capacity to preserve cognitive function in PD models, employing combinatorial experimental approaches to elucidate the interplay between STING signaling and O-GlcNAc homeostasis.