This study aims to investigate the role of mitochondrial-related gene Methionine sulfoxide reductase B2 (MsrB2) in the pathogenesis of systemic lupus erythematosus (SLE) and assess its potential as a diagnostic biomarker. We validated their expression profiles and clinical significance through experimental analyses, and sought to provide novel biomarkers for the diagnosis, classification, and treatment of SLE.

1. The expression of MsrB2 in peripheral blood mononuclear cells (PBMCs) and plasma from both SLE patients and healthy controls was assessed using quantitative PCR (qPCR), Western blotting (WB), flow cytometry, and enzyme-linked immunosorbent assay (ELISA). The correlation between MsrB2 expression levels and clinical indicators was analyzed to evaluate its diagnostic efficacy.

2. The MRL/lpr lupus mouse model was utilized to evaluate MsrB2 expression in the kidney, spleen, and lymph nodes. Assessment techniques included Enzyme-Linked Immunosorbent Assay (ELISA), Western Blot (WB), flow cytometry, Hematoxylin and Eosin staining (HE), Masson staining, Periodic Acid-Schiff staining (PAS), and immunofluorescence (IF).

1. Experimental validation showed significantly elevated MsrB2 expression in PBMC and plasma of SLE patients compared to healthy controls. Specifically, MsrB2 RNA expression in PBMC was positively correlated with triglycerides, cholesterol, interleukin 17 (IL-17), NK cell proportions, and ferritin, and negatively correlated with free thyroxine (FT4) levels. Plasma MsrB2 protein levels were positively correlated with anti-cardiolipin antibody IgG, anti-β2 glycoprotein I IgG antibody, and interleukin 12 p70 (IL-12 p70), and negatively correlated with C-reactive protein (CRP) and FT4.

2. Flow cytometry analysis revealed an increased proportion of classical monocytes in SLE patients, whereas the proportion of MsrB2⁺ classical monocytes was lower than in controls, potentially indicating decreased antioxidant capacity and enhanced inflammatory response.

3. The MRL/lpr lupus mouse model exhibited hallmark features of SLE, including splenomegaly, lymph node hyperplasia, elevated anti-nuclear and anti-double-stranded DNA antibodies, and renal impairment. Renal mitochondrial autophagy-related protein Sequestosome-1 (P62) was down-regulated, while autophagy marker LC3-II and Parkin RBR E3 Ubiquitin Protein Ligase (Parkin) were up-regulated, indicating enhanced mitochondrial autophagic flux. Additionally, there was a significant increase in the percentage of Ly6C^hi monocytes in peripheral blood, highlighting immune activation associated with SLE. Immunofluorescence analysis revealed a marked upregulation of MsrB2 expression in the kidney, spleen, and lymph nodes.

This study systematically delineates the expression profile and functional potential of the mitochondrial-associated gene MsrB2 in SLE. MsrB2 expression was markedly elevated in both PBMCs and plasma of SLE patients and was strongly correlated with a range of immune, inflammatory, and metabolic parameters, indicating its potential as a diagnostic biomarker and therapeutic target. Flow cytometric analysis revealed an increased frequency of MsrB2⁺ non-classical monocytes, alongside reduced MsrB2 expression in classical monocytes, suggesting its involvement in shaping monocyte subset phenotypes and antioxidant capacity. In the MRL/lpr lupus mouse model, MsrB2 was significantly upregulated in the kidney, spleen, and lymph nodes, coinciding with enhanced mitophagy and an accumulation of pro-inflammatory Ly6C^hi monocytes, further supporting its role as a mediator of SLE immunopathology. Collectively, these findings suggest that MsrB2 contributes to SLE pathogenesis through the regulation of mitochondrial homeostasis, autophagy, and monocyte-driven immune activation, positioning it as a promising molecular target for mechanistic investigation in SLE. Future studies involving larger patient cohorts and in-depth mechanistic analyses are warranted to validate its clinical applicability.