Cells evolved to detect foreign DNA and respond with inflammatory signaling. Unfortunately aging brings with it the mislocalization of fragments of the cell's own DNA that is then misidentified as foreign, triggering these same inflammatory pathways. This response, and a number of other responses to forms of damage inside the cell, converge on the regulatory protein STING. The activity of STING that leads to inflammation is thus an interesting target for the treatment of age-related conditions involving excessive chronic inflammation. As for near all of the present potential approaches to the chronic inflammation of aging, sabotaging STING will harm the normal innate immune response to infection, cancer, and so forth. This may be worth it in some scenarios. The use of biologics for patients with rheumatoid arthritis shows how this will likely play out: long term and more subtle harms to immune function and health are accepted when short term, evident benefits can be realized.
The stimulator of interferon genes (STING) plays a crucial role as an adaptor in innate immune defense, orchestrating key inflammatory processes through the modulation of type I interferon signaling and activation of cytokine networks. Recent studies have identified STING-induced neuroinflammatory responses as a major factor in the progression of neurological diseases, particularly in neurodegenerative disorders.
This review methodically explores the structural basis of STING activation and its role in driving pathological inflammation. The classic and non-classic pathways of STING as well as their roles in neurodegenerative diseases were discussed. Additionally, it critically assesses new pharmacological approaches that target the STING pathway, emphasizing anti-inflammatory treatments ranging from synthetic small-molecule inhibitors to bioactive natural compounds, which aim to mitigate neurotoxic inflammation.
By combining mechanistic insights with therapeutic advancements, this paper presents an innovative transformation framework aimed at developing anti-inflammatory therapies targeting the STING pathway to treat neurodegenerative diseases. The core contribution of this framework lies in systematically bridging the innate immune regulation and neuroinflammation control mechanisms, providing a new strategy for disease intervention.
Link: https://doi.org/10.3389/fnagi.2025.1659216
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