A novel dual-target approach for Parkinson’s disease therapy by the novel immunomodulator 3-monothiopomalidomide

α-Synuclein (αSyn) aggregation is a central driver for Parkinson’s disease (PD), leading to the formation of toxic oligomeric species that promote microglial reactivity and establish a self-sustaining cycle of neuroinflammation and neurodegeneration. This process accelerates dopaminergic neuron loss in the substantia nigra and contributes to motor and cognitive deficits. Targeting both αSyn aggregation and inflammation represents a promising therapeutic strategy. This study evaluated 3-monothiopomalidomide (3MP), a novel immunomodulatory imide drug with improved safety over Pomalidomide. In vitro, 3MP reduced αSyn–induced neuronal death, microglial activation, and inflammation. Thioflavin T assay and Thioflavin S staining in SH-SY5Y cells showed significant inhibition of αSyn aggregation. In vivo, chronic administration in a αSyn-based PD rat model preserved dopaminergic neurons, improved motor and cognitive function, reduced αSyn aggregates and neuroinflammation in the midbrain and anterior cingulate cortex. Overall, 3MP shows strong dual-action potential by modulating both αSyn aggregation and neuroinflammation, supporting its development as a disease-modifying therapy for PD.