Novel in silico Evidence of Bisphenol A as a Neuroinflammatory Modulator through the cGAS-STING-NLRP3 Pathway.

Bisphenol A (BPA), a widely prevalent environmental contaminant, has been linked to neuroinflammation; however, the molecular mechanisms underlying this effect remain unclear. In this study, we used molecular docking and molecular dynamics simulations to predict the interactions of BPA with key proteins in the cGAS-STING-NLRP3 signaling pathway, an innate immune axis implicated in neuroinflammatory diseases. BPA demonstrated higher predicted binding affinity to these proteins than the reference neurotoxicant rotenone, suggesting a potential to interact with and modulate this pathway. Molecular dynamics simulations indicated stable binding of BPA, with possible structural adaptations observed in cGAS and NLRP3 proteins, which may influence downstream inflammatory signaling. Since this pathway plays a role in neurodegeneration by sensing cytosolic DNA and activating the NLRP3 inflammasome and type I interferon responses, our computational findings raise the possibility of a previously unrecognized route for BPA-mediated neuroimmune modulation, distinct from oxidative stress or NF-κB activation. These predictions underscore the need for further experimental validation and provide a basis for future research into the mechanistic underpinnings and therapeutic targeting of BPA-induced neurotoxicity.