LRRK2 regulates ferroptosis through the system Xc‐GSH–GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease

Abstract Parkinson's disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine‐rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation, however, the effect of LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activating nuclear factor‐κB. Inhibition of LRRK2 expression effectively suppressed the LPS‐induced pro‐inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co‐overexpressing LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc‐GSH–GPX4 pathway as a crucial component in LRRK2‐mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH‐SY5Y cell apoptosis. Additionally, we observed abundant expression of LRRK2 and P‐P65 in the midbrain, which was elevated in the MPTP‐induced PD model, along with microglia activation. LRRK2 and P‐P65 expression inhibition with PF‐06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP‐treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc‐GSH–GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.