Urocanic Acid Alleviates Cognitive Impairment by Targeting ZCCHC3 and Suppressing the cGAS-STING-Mediated Senescence

This study aimed to investigate the role of urocanic acid (UCA) modulates cognitive impairment in a D-galactose (DG)-induced aging model, providing new insights and a theoretical foundation for the treatment of related diseases. Mouse senescence and astrocyte model was created by DG-induced stimuli to assess the effects of UCA. Molecular docking was utilized to confirm potential targets of UCA, and the interaction was validated using the Drug Affinity Responsive Target Stability assay combined with Western blot analysis. The molecular mechanism of UCA was elucidated through in vivo and in vitro experiments. The result showed that UCA treatment ameliorated learning and memory capabilities in DG-induced mice, maintains astrocyte morphology while reducing Apoptosis and senescent cells, and inflammatory factors. Additionally, UCA treatment alleviated cell cycle arrest. Molecular docking revealed direct binding between UCA and the ZCCHC3 protein. ZCCHC3 overexpression exacerbated cellular senescence, increased Apoptosis and senescent cells, and inflammatory factor levels, while simultaneously activating the Cyclic GMP-AMP Synthase (cGAS)/stimulator of interferon genes (STING) pathway. UCA treatment reversed the effects of ZCCHC3 overexpression. Mechanistically, UCA inhibited the cGAS/STING pathway by binding to ZCCHC3, thereby alleviating cellular senescence. In vivo experiments further confirmed that ZCCHC3 overexpression or exogenous cGAS activation negated the cognitive protective effects of UCA. The study demonstrates that UCA alleviates cognitive impairment and astrocyte senescence by directly binding to ZCCHC3 to suppress the cGAS‑STING pathway. These results identify ZCCHC3 as a novel therapeutic target and clarify the molecular basis of related disorders.raci.

Astrocyte senescence; Cognitive impairment; Urocanic acid; ZCCHC3; cGAS-STING.