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Over the past 2\u2009decades, work has shown that cytosolic DNA sensing via the cGAS\u2013STING pathway can precondition the brain against ischemic injury while impairing post-stroke recovery. Our interest in this pathway arose from the discovery that tilorone, an antiviral immunomodulator, activated a hypoxia-inducible factor (HIF) reporter. Although pre-stroke tilorone treatment was strongly neuroprotective, mechanistic studies revealed that type I interferon (IFN-I) signaling\u2014rather than canonical HIF activation\u2014mediated this effect. However, STING activation can also impair learning and memory. We therefore review the Janus-like duality of cGAS\u2013STING signaling: transient activation enhances ischemic tolerance, whereas sustained activation suppresses neuronal plasticity. In contrast to HIF-driven metabolic reprogramming and growth factor induction, we propose that cGAS\u2013STING\/IFN-I signaling enforces a metabolic austerity program that suppresses energy-intensive processes such as synaptic plasticity. This response is adaptive during ischemia but maladaptive when prolonged, locking neural circuits into a low-plasticity state that undermines cognitive resilience. Evidence across models of stroke, neurodegeneration, aging, demyelination, and traumatic injury highlights both the protective and pathological consequences of this pathway and underscores the need to balance innate immune defense with long-term brain health.<\/jats:p>","DOI":"10.1177\/0271678x261427904","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:51:16Z","timestamp":1773309076000},"page":"2901-2912","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective and pathogenic: The Janus-faced role of cGAS\u2013STING in the brain"],"prefix":"10.1177","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-3046","authenticated-orcid":false,"given":"Carlo","family":"Corona","sequence":"first","affiliation":[{"name":"Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY, USA"},{"name":"Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Kanzlemar","sequence":"additional","affiliation":[{"name":"Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3921-9021","authenticated-orcid":false,"given":"Abid","family":"Hussaini","sequence":"additional","affiliation":[{"name":"Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY, USA"},{"name":"Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9081-2701","authenticated-orcid":false,"given":"Rajiv R","family":"Ratan","sequence":"additional","affiliation":[{"name":"Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY, USA"},{"name":"Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","unstructured":"Mattson MP. 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