Zmiz1-Mediated SUMOylation of NLRP3 Inflammasome Regulates Satellite Glial Cell Activation and Neuronal Autophagy in Trigeminal Neuralgia

Trigeminal neuralgia (TN) is characterized by neuroinflammation and satellite glial cell (SGC) activation, but the molecular mechanisms remain unclear. This study identifies zinc finger MIZ-type containing 1 (Zmiz1) as a key regulator that promotes SUMOylation of NLRP3 inflammasome, thereby influencing SGC activation and neuronal autophagy in TN. Using bioinformatics analysis, we identified Zmiz1 as a key SUMOylation-related gene involved in TN. Single-cell transcriptomics and co-expression network analysis revealed Zmiz1 enrichment in SGCs and neurons. Co-immunoprecipitation (Co-IP) and western blotting confirmed Zmiz1's interaction with NLRP3 and its role in promoting NLRP3 SUMOylation. In vitro experiments assessed the impact of Zmiz1 overexpression and knockdown on SGC activation, inflammatory cytokine secretion, and neuronal autophagy. A TN rat model was established to evaluate pain behavior, neuroinflammation, and neuronal apoptosis. Zmiz1 overexpression significantly enhanced NLRP3 SUMOylation, promoting SGC activation and inflammation while inhibiting neuronal autophagy. Conversely, silencing Zmiz1 reduced neuroinflammation and improved neuronal viability. In vivo, Zmiz1 knockdown alleviated TN-associated pain hypersensitivity and neuronal apoptosis. This study unveils a novel mechanism by which Zmiz1 regulates TN via NLRP3 SUMOylation, highlighting the Zmiz1/NLRP3 axis as a potential therapeutic target for TN treatment.