Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson’s disease via the tim-3/NF-κb axis

Microglia-mediated neuroinflammation is a critical driver of dopaminergic neuronal loss in Parkinson's disease (PD), presenting a viable target for disease-modifying therapies. Although the transcription factor Spi-1 proto-oncogene (SPI1) is implicated in microglial regulation, its specific pathological role and therapeutic potential in PD remain elusive. In this study, utilizing in vivo MPTP-induced mouse models and in vitro MPP + stimulated microglia, we identified SPI1 as a crucial regulator of PD-associated neuroinflammation. We found that SPI1 expression is aberrantly upregulated in both PD models. Crucially, SPI1 knockdown significantly mitigated motor deficits, attenuated dopaminergic neuronal loss, and suppressed neuroinflammation by reducing proinflammatory cytokines. Mechanistically, we revealed that SPI1 directly binds to the promoter of T-cell immunoglobulin and mucin-domain-containing 3 (TIM-3) to activate its transcription. Silencing SPI1 facilitated a neuroprotective microglial M1-to-M2 phenotypic shift by downregulating TIM-3 and subsequently inhibiting the NF-κB signaling pathway, thereby protecting against synaptic impairment and neuronal apoptosis. Together, our findings elucidate a novel SPI1/TIM-3/NF-κB regulatory axis in microglial polarization and highlight the targeted inhibition of SPI1 as a promising therapeutic strategy for ameliorating neuroinflammation and halting disease progression in Parkinson's disease.