Systemic lupus erythematosus (SLE) is a complex autoimmune disease often complicated by lupus nephritis (LN), a major cause of morbidity. Emerging evidence suggests that dysregulated iron metabolism and renal iron accumulation may contribute to SLE pathogenesis. This study aims to investigate the therapeutic effects and underlying mechanisms of an iron-restricted diet in SLE, with a focus on renal injury, inflammation, lipid peroxidation, and iron homeostasis.

Female MRL/lpr mice, a spontaneous model of SLE, were fed either an iron-restricted diet (8 mg/kg iron) or a normal control diet (360 mg/kg iron) from 8 to 16 weeks of age. Healthy MRL/MpJ mice served as controls. Disease progression was monitored by assessing proteinuria, serum autoantibodies (ANA, anti-dsDNA), and inflammatory cytokines (IL-1β, IL-18). Renal pathology was evaluated using H&E, Masson's trichrome staining, and transmission electron microscopy. Renal iron accumulation, lipid peroxidation (MDA), glutathione (GSH), and expression of NLRP3 and GPX4 were measured. In parallel, transcriptomic analysis of iron homeostasis-related genes was performed using publicly available gene expression datasets from pediatric and adult SLE patients. Two-sample Mendelian randomization (MR) analysis was conducted to assess the genetic association between iron status biomarkers and SLE risk.

Iron-restricted diet significantly reduced proteinuria and attenuated renal pathological damage, including glomerular swelling, tubular dilation, tubulointerstitial fibrosis, podocyte effacement, and mitochondrial abnormalities in MRL/lpr mice, without affecting body weight. It also decreased renal tubulointerstitial iron accumulation, suppressed NLRP3 inflammasome activation, and reduced serum IL-1β and IL-18 levels. Additionally, the diet lowered renal malondialdehyde (MDA) content and upregulated GPX4 expression, indicating reduced lipid peroxidation. Transcriptomic analysis revealed widespread dysregulation of iron metabolism genes in SLE patients, including altered expression of iron uptake (e.g., LCN2, SLC39A14), efflux (e.g., SLC40A1), and storage pathways, with distinct patterns between pediatric and adult patients. MR analysis showed no robust causal association between genetically predicted iron status and SLE risk, although suggestive trends were observed for iron deficiency traits.

Iron-restricted diet effectively alleviates renal injury, suppresses inflammation, and reduces lipid peroxidation in lupus-prone mice, likely through modulation of iron accumulation and ferroptosis-related pathways. These findings highlight the potential of dietary iron restriction as a simple, safe, and accessible adjunctive intervention for SLE management. Further studies are warranted to validate its clinical applicability and long-term safety.