〔Abstract〕 Objective To investigate the regulatory mechanism of peptidylarginine deiminase 4 (PADI4) on matrix metalloproteinase (MMPs) expression and its potential role in the development of systemic lupus erythematosus (SLE). Methods ThemRNA expression levels of MMP-14/17/25 in SLE patients and healthy controls (HC) were measured by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-qPCR), and their serum protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Spearman's rank correlation analysis was used to evaluate the correlations between MMPs levels and clinical parameters in SLE patients. Primary neutrophils were treated with the PADI4 inhibitor GSK484, or MMPs expression levels were examined in PADI4-knockdown neutrophil-like HL-60 (dHL-60) cells, and cell migration ability was assessed by wound healing assay. Results The mRNA expression levels of MMP- 14/17/25 in neutrophils from SLE patients were lower than those in the HC (all P<0.01). Serum levels of these three MMPs were also lower than those in the HC (all P<0.01). MMP-14 levels were negatively correlated with immunoglobulin G (IgG) (r=-0.266), immunoglobulin A (IgA) (r=- 0.286), and globulin (GLB)(r=-0.269) (all P<0.05), while both MMP-17 (r =-0.269) and MMP- 25(r =-0.244) levels were negatively correlated with urinary protein (UTP) (all P<0.05). After treatment with GSK484 (10 μmol/L) to inhibit PADI4 activity, the protein expression levels of MMP-14/17/25 in neutrophils were higher than those in the Vehicle group (all P<0.05), and the cell migration rate in wound healing assay was also greater than that in the Vehicle group (P<0.01). Furthermore, after knockdown of PADI4 expression, the mRNA expression levels of MMP- 14/17/25 were higher than those in the Vehicle group (all P<0.05). Conclusion MMP-14/17/25 are downregulated in SLE and negatively regulated by PADI4. PADI4 may contribute to SLE progression by suppressing MMPs expression and neutrophil migration. These findings suggest that MMPs may serve as novel biomarkers and therapeutic targets for SLE.