Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease whose pathogenesis is closely associated with genetic susceptibility and immune dysregulation. Ferroptosis, a novel form of programmed cell death, has been increasingly implicated in autoimmunity, yet its genetic causal role in SLE remains unclear.

Objectives: This study aims to systematically screen ferroptosis-related genes causally associated with SLE pathogenesis using genome-wide association studies (GWAS) and transcriptomic data, and to explore the potential downstream pathways of the core gene, RNASET2 .

Methods: A total of 933 ferroptosis-related genes were obtained from the FerrDb database. Their expression quantitative trait loci (eQTLs) in peripheral blood were used for Mendelian randomization (MR) to identify genes causally linked to SLE. External validation was performed using alternative SLE GWAS datasets. Cell-specific eQTLs from 14 types of immune cells were separately subjected to MR analysis with SLE to identify the specific immune cell types in which key genes exert their effects. Differential expression of key genes across immune cell subsets was validated using bulk RNA-seq and scRNA-seq data from the patients with SLE. Correlation analysis between key genes and classical ferroptosis markers was conducted to infer downstream mechanisms.

Results: Ribonuclease T2 ( RNASET2 ) was the most significant gene negatively associated with SLE, with higher expression levels conferring a protective effect against SLE. Low expression of RNASET2 in dendritic cells, natural killer cells, and T cells may inhibit the activity of the ferritin key subunit FTH1, leading to lipid peroxidation and promoting ferroptosis.

Conclusions: Through systematic multi-omics analysis, this study provides the genetic evidence that reduced RNASET2 activity in dendritic cells, NK cells, and T cells may increase the risk of SLE through ferroptosis.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.