Expression Profile and Clinical Significance of Ferroptosis-Related Genes in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis.

Abstract

Introduction: Systemic sclerosis (SSc) is a severe autoimmune disease marked by immune dysregulation and progressive fibrosis, yet reliable blood biomarkers remain limited. Ferroptosis, an iron‑dependent lipid peroxidation-driven cell death pathway, links iron/redox imbalance to inflammation and fibrotic remodeling, but its role in SSc is poorly defined. To profile Ferroptosis‑Related Genes (FRGs) in Peripheral Blood Mononuclear Cells (PBMCs) from SSc patients and assess their clinical significance.

Methods: Transcriptional profiles from four SSc patients and six Healthy Controls (HCs) were analyzed using the Arraystar Human LncRNA Microarray to identify Differentially Expressed Genes (DEGs). Ferroptosis-related DEGs in SSc (Ferr-DEGs) were obtained by intersecting DEGs with a ferroptosis database, and key Ferr-DEGs were prioritized using bioinformatic analyses. Immune cell infiltration was estimated using single-sample gene set enrichment analysis (ssGSEA). The expression of selected genes was validated by quantitative real-time polymerase chain reaction (RT-qPCR) in an expanded cohort (SSc = 36, HC = 36), and correlations with clinical indicators were assessed. Diagnostic performance was evaluated using ROC curves.

Results: Microarray analysis revealed 397 upregulated and 637 downregulated DEGs in the SSc group. Bioinformatic analyses identified eight ferroptosis-associated key genes in SSc: MAPK14, SRC, ATF3, CYBB, ACSL1, STK11, PLIN2, and NCF2. MAPK14, SRC, ATF3, and CYBB were significantly upregulated in SSc compared with HCs, whereas ACSL1 was downregulated. Notably, SRC showed good diagnostic performance for SSc, with an AUC of 0.891 (95% CI, 0.819-0.964).

Discussion: Given the emerging link between ferroptosis and autoimmune diseases, exploring its role in the pathogenesis of Systemic Sclerosis (SSc) could open new avenues for improving diagnostic and therapeutic strategies.

Conclusions: Our findings indicate significant dysregulation of FRGs in PBMCs from SSc patients, suggesting their potential involvement in inflammation, immune cell infiltration, and fibrosis; notably, SRC may serve as a candidate diagnostic marker for SSc.