Targeting BCL11B-mediated JAK2/STAT3 activation: A novel therapeutic strategy for Parkinson’s disease

Parkinson's disease (PD) is driven in part by neuroinflammation. We investigated whether the transcription factor BCL11B contributes to dopaminergic neurodegeneration in this context. Transcriptome sequencing of MPTP-induced PD mice revealed BCL11B upregulation, which was confirmed in MPP + -treated MN9D cells, MPTP-lesioned mice, and dopaminergic neurons exposed to inflammatory conditioned medium. BCL11B knockdown attenuated dopaminergic neuron loss, reduced apoptosis, improved motor deficits, and partially blocked JAK2/STAT3 pathway activation in both inflammatory and MPTP-induced PD models. Mechanistically, BCL11B mediated neurotoxicity through the JAK2/STAT3 pathway, with acetylation modifications potentially modulating its activity. These findings establish BCL11B as a key regulator of neuroinflammation and dopaminergic survival in PD, and suggest that targeting BCL11B may offer a therapeutic approach for this neurodegenerative disease.