Targeting the cGAS–STING Pathway Mitigates Huntington Disease Pathogenesis in a Knock-In Mouse Model

Cyclic GMP–AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), form a central cytosolic DNA–sensing pathway that drives innate immune activation and pro-inflammatory cytokine production. We previously reported that cGAS is upregulated in Huntington disease (HD) cellular models, where it modulates autophagy and inflammatory signaling. However, its in vivo contribution to HD pathogenesis has remained unresolved. Here, we genetically ablated cGAS in zQ175 knock-in HD mice, a model that closely recapitulates hallmark features of human HD, and conducted longitudinal behavioral analyses from 2 to 14 months of age. cGAS deletion significantly ameliorated HD-associated motor impairments, as evidenced by improved rotarod performance, enhanced coordination on beam walk, and better outcomes across a comprehensive behavioral battery. It also mitigated the progressive body-weight loss characteristic of zQ175 mice. Analysis of brain sections further revealed that cGAS deletion reduced the enlargement of lateral ventricles and attenuated both astrogliosis and microgliosis in the striatum. While cGAS loss produced minimal effects in wild-type littermates, transcriptomic profiling of HD brains showed downregulation of genes associated with development and cell–cell communication (Mid1-ps1, Slc45a3, Ilvbl, Col5a3) and upregulation of transcripts linked to ion transport and synaptic activity (Pgam2, Nos1, Cort, RasGef1a). Targeted lipidomics uncovered elevated levels of bioactive immunoregulatory lipids—particularly 12-HETE (ω-6) and 12-HEPE (ω-3)—in HD mice lacking cGAS. Finally, to assess therapeutic potential of cGAS-STING pathway, we pharmacologically inhibited STING using H-151 in zQ175 mice, which led to improved age-dependent motor performance. Collectively, these findings identify cGAS as a critical contributor to HD pathogenesis and support cGAS–STING pathway inhibition as a promising therapeutic avenue for Huntington disease.