Targeting the cGAS–STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model

Abstract

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.