Ferroptosis-Based Peripheral Immune Dysregulation and Diagnostic Signatures in Parkinson's Disease: An RNA Transcriptomic and Single-Cell Immune Sequencing Analysis.

Parkinson's disease (PD) is a common neurodegenerative disorder in which ferroptosis and immune dysregulation have been implicated. However, the crosstalk between ferroptosis-related transcriptional signatures and peripheral immune alterations in PD remain unclear. Herein, we integrated bulk transcriptomic datasets and a peripheral blood single-cell dataset to identify ferroptosis-related genes associated with PD and to evaluate their diagnostic potential. Initially, we identified 16 abnormally expressed ferroptosis-related genes (AEFRGs) associated with peripheral immune cell infiltration in PD. Then a LASSO-derived 15-gene signature was established, which showed high discriminatory performance in the discovery dataset and in two validation datasets, including an independent blood dataset and a substantia nigra dataset. Consensus clustering of PD samples based on 276 ferroptosis-related genes (FRGs) stratified PD patients into three molecular subtypes with different diagnostic scores, immune scores, immune-related factors, and cell-death/oxidative-stress pathway enrichment. The imumue cell infiltration analysis indicated low level of macrophage and high level of B cell in PD patients' perioheral blood. Peripheral blood single-cell analysis localized ferroptosis-related transcriptional features mainly related to NK cells, CD4+ T cells and CD8+ T cells in PD patients with significant difference of RPL8 and ATM, and identified 9 key characteristic ferroptosis genes (CFGs). In rotenone-treated human neuroblastoma SH-SY5Y cells, the CFGs inculding XBP1, SCP2, GABARAPL1, DUSP1, HSPA5 and HERPUD1 were increased, whereas UBC, RPL8 and ATM were not significantly changed. Collectively, these findings suggest that ferroptosis-related transcriptional signatures may reflect peripheral immune dysregulation and provide candidate diagnostic markers for PD.