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 key cytosolic DNA-sensing pathway that drives innate immune activation and proinflammatory signaling. We previously showed that cGAS is upregulated in Huntington disease (HD) cellular models, where it regulates autophagy and inflammation; however, its in vivo role remained unclear. Here, we genetically ablated cGAS in Q175DN knock-in HD mice and performed longitudinal behavioral assessments from 2 to 14 mo of age. cGAS deletion significantly improved HD-associated motor deficits, including rotarod performance and beam-walk coordination, and mitigated progressive body-weight loss. Histological analyses revealed reduced lateral ventricle enlargement and decreased striatal astrogliosis and microgliosis. While minimal effects were observed in wild-type littermates, transcriptomic profiling of HD brains lacking cGAS showed downregulation of genes involved in development and cell-cell communication, along with upregulation of genes linked to ion transport and synaptic function. Lipidomic analysis further demonstrated increased levels of immunoregulatory lipids, particularly 12-HETE and 12-HEPE, indicating a shift toward a protective lipid profile. Importantly, pharmacological inhibition of STING using H-151 improved age-dependent motor performance, reduced striatal atrophy, and attenuated glial cell activation in Q175DN mice. Collectively, these findings identify the cGAS-STING pathway as a critical driver of HD progression and support its inhibition as a promising therapeutic strategy.