Berberine Attenuates Microglial Inflammation by Targeting the SAE1/UBA2 Complex and Suppressing NLRP3 SUMOylation

Background Neuroinflammation contributes to the pathogenesis of multiple neurodegenerative diseases. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is regulated by posttranslational modifications, including small ubiquitin-like modifier (SUMO)ylation initiated by the SAE1/UBA2 complex. Purpose To investigate whether berberine (BBR) attenuates microglial inflammation by modulating SAE1/UBA2-associated NLRP3 SUMOylation. Materials and Methods Molecular docking was performed to predict interactions between BBR and the SAE1/UBA2 complex. An inflammatory model was established in BV2 microglia using lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Cell viability, cytokine secretion, and apoptosis were evaluated using cell counting kit-8 assays, enzyme-linked immunosorbent assays, and flow cytometry, respectively. Western blotting and coimmunoprecipitation were used to examine inflammasome-related proteins and NLRP3 SUMOylation. Results Molecular docking predicted a potential interaction between BBR and the SAE1/UBA2 complex, with a docking score of −6.747 kcal/mol. BBR improved cell viability and reduced interleukin-1β and interleukin-18 secretion and apoptosis in LPS/ATP-stimulated BV2 cells. SAE1 overexpression aggravated inflammatory responses, whereas BBR partially reversed these effects. BBR also reduced NLRP3 SUMOylation and attenuated ASC expression and caspase-1 activation. Conclusion BBR attenuates LPS/ATP-induced inflammatory responses in BV2 microglia, potentially through modulation of SAE1/UBA2-associated NLRP3 SUMOylation and inflammasome activation.