cGAS-mediated IFN-I signaling contributes to disease progression in drug-refractory epilepsy
Epilepsy is a prevalent neurological disease with a third of patients becoming non-responsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we report that DRE disease progression is contributed by overactive cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN-I) signaling. In human DRE microglia, we observe a robust IFN-I signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we observe the activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS reduces epileptic phenotypes, glial inflammatory signatures, and neuronal transcriptomic changes, underscoring the therapeutic potential of targeting cGAS for DRE treatment.
Authors
- Subhash C. Sinha (ORCID: https://orcid.org/0000-0001-8916-5677)
- Zhuofan Lei (ORCID: https://orcid.org/0000-0002-4207-2796)
- Benjamin Liechty (ORCID: https://orcid.org/0000-0001-6485-5604)
- Man Ying Wong (ORCID: https://orcid.org/0000-0002-2165-9328)
- Daphne Zhu
- Nagiri Ravi Kumar (ORCID: https://orcid.org/0000-0002-4531-8288)
- Mika P. Cadiz (ORCID: https://orcid.org/0000-0002-8894-4940)
- Sadaf Amin (ORCID: https://orcid.org/0000-0002-3758-6485)
- Y. H. D. Lee
- Shiaoching Gong (ORCID: https://orcid.org/0000-0002-5907-5539)
- Balaji Krishnamachary (ORCID: https://orcid.org/0000-0001-6137-5832)
- H LI
- H Li
- Hao Chen (ORCID: https://orcid.org/0000-0003-3296-670X)
- Li Gan (ORCID: https://orcid.org/0000-0002-9250-7807)
- Kelli Lauderdale (ORCID: https://orcid.org/0000-0002-1943-7128)
- Jorge J Palop
- Jingjie Zhu
- Pearly Ye
- Wenjie Luo
- Li Fan
- Yige Huang
- Maitreyee Bhagwat
- Kendra Norman
Institutions
- University of Maryland, Baltimore (US)
- Gladstone Institutes (US)
- NewYork–Presbyterian Hospital (US)
- Cornell University (US)
- New York Hospital Queens (US)
- Presbyterian Hospital (US)
- MIND Research Institute (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-02
- DOI
- https://doi.org/10.64898/2026.01.30.702860
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 24.43