Elucidating the molecular mechanisms underlying the therapeutic effects of 6-shogaol on Parkinson’s disease

Ginger has beneficial effects on brain health and neurodegenerative diseases, including Parkinson's disease (PD). Among its constituents, 6-shogaol has been identified as a major bioactive compound; however, the molecular mechanisms underlying its neuroprotective effects in PD remain unclear. This study aimed to explore the potential signaling mechanisms associated with the effects of 6-shogaol in PD. RNA sequencing was performed to identify transcriptional changes induced by 6-shogaol. Network pharmacology was used to predict shared targets between 6-shogaol and PD, and molecular docking was conducted to evaluate potential interactions with candidate targets. BV2 microglial cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model were used for biological validation. RNA sequencing analysis revealed that 6-shogaol significantly modulates inflammatory transcriptional networks and is associated with suppression of the Jak/STAT signaling pathway. Network pharmacology identified 58 overlapping targets between 6-shogaol and PD, with STAT3 emerging as a central hub in the interaction network. Molecular docking suggested a potential interaction between 6-shogaol and STAT3. Experimental validation showed that 6-shogaol reduced STAT3 phosphorylation and decreased pro-inflammatory mediators in BV2 cells. In the MPTP-induced PD mouse model, 6-shogaol improved motor performance, protected dopaminergic neurons, reduced glial activation, and attenuated Jak2/STAT3 phosphorylation in the brain. Together, these findings suggest that the neuroprotective effects of 6-shogaol may be associated with modulation of STAT3-associated inflammatory signaling, supporting its potential therapeutic relevance in PD.