2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is a pervasive environmental brominated flame retardant that accumulates in nervous tissues and induces persistent neurotoxicity. Emerging evidence indicates that PBDE-47 perturbs neuronal autophagy, yet the definitive upstream molecular mechanism remains uncharacterized, hindering the development of effective protective strategies. This study was performed to clarify the toxic regulatory cascade and explore feasible pharmacological interventions using in vivo neonatal rat hippocampal tissue and in vitro PC12 neuronal cell models. Animals were neonatally exposed to PBDE-47 (0.1, 1.0, 10.0 mg/kg·bw), and PC12 cells were treated with PBDE-47 (1, 10, 20 µM) for mechanistic exploration. Results showed that PBDE-47 dose-dependently upregulated histone deacetylase 6 (HDAC6), decreased α-tubulin (K40) acetylation, and destabilized neuronal microtubules. Such microtubule structural damage impaired autophagosome retrograde trafficking, blocked autophagosome-lysosome fusion, and eventually caused neuronal loss, synaptic protein reduction, and cognitive impairment. For mechanism validation and rescue experiments, 1 mg/kg·bw paclitaxel (PTX) and 1 mg/kg·bw tubastatin A (TBA) were administered to neonatal rats, whereas 12.5 nmol/L PTX and 10 µmol/L TBA were used for PC12 cell treatment to stabilize microtubules and selectively inhibit HDAC6, respectively. Both pharmacological interventions effectively restored tubulin acetylation, rescued defective autophagic flux, and mitigated PBDE-47-induced neuronal injury, with TBA showing better applicability due to its high blood-brain barrier permeability and biosafety. Behavioral tests in vivo verified that PTX and TBA treatment significantly ameliorated PBDE-47-elicited learning and memory deficits. Collectively, these findings define the HDAC6/microtubule acetylation axis as a core upstream pathway responsible for PBDE-47-triggered autophagic transport failure and neurotoxicity, providing robust experimental evidence and a promising therapeutic target for the prevention of PBDEs-mediated neurological disorders.
