Organophosphate Flame Retardants Induce Neurodegenerative Pathologies by Paralyzing HSP90AB1 Chaperone Function: A Multi-Scale Computational and Biophysical Study

Abstract This study integrated computational toxicology with biophysical and cellular validation to investigate the neurotoxic potential of 10 flame-retardant-related compounds. ADMETlab 3.0 predicted blood-brain barrier probabilities of 0.989 for bis(1,3-dichloro-2-propyl) phosphate and 0.444 for diphenyl phosphate (DPHP), interpreted as screening predictions. Network topology analysis identified HSP90AB1 as a shared candidate hub target linking organophosphate flame retardants to Alzheimer’s and Parkinson’s diseases. Molecular dynamics simulations indicated a stable HSP90AB1 backbone in the DPHP complex (root-mean-square deviation ∼0.18 nm). Surface plasmon resonance measured an equilibrium dissociation constant of 1.49 μM. DPHP induced dose-dependent cytotoxicity in neuronal cells; the half-maximal inhibitory concentration was not determined within the tested range. HSP90AB1 overexpression mitigated DPHP-induced reactive oxygen species production and transcriptional upregulation of pro-apoptotic and pro-inflammatory genes. Single-cell virtual knockout identified candidate regulatory processes; Parkinson’s disease-related enrichment remained exploratory after multiple-testing correction. Together, the computational, biophysical, and cellular findings support HSP90AB1 as a candidate target of environmental neurotoxicity and motivate further investigation of DPHP.