Ferroptosis‐Based Peripheral Immune Dysregulation and Diagnostic Signatures in Parkinson's Disease: An
RNA
Transcriptomic and Single‐Cell Immune Sequencing Analysis
Lei Cheng, Jing Zhang, Wen‐Ting Shi, Qing Ye, Chen Huang, Zhong‐Yan Zhou ABSTRACT
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.