Systemic lupus erythematosus (SLE) is an autoimmune disease where patients produce autoantibodies against DNA, histones, and neutrophil proteins, leading to immune complex formation and lupus nephritis. Neutrophils release extracellular traps (NETs) during infections, which are made of DNA, histones, and neutrophil proteins. Timely degradation of NETs is crucial for tissue homeostasis and preventing self-antigen presentation. This study shows that serum DNase1 is essential for NET degradation. In SLE patients, impaired NET degradation is linked to kidney involvement. Two mechanisms cause this: (i) DNase1 inhibitors in SLE sera, and (ii) anti-NET antibodies that prevent DNase1 access to NETs. Impaired DNase1 function and poor NET degradation correlate with kidney involvement. Identification of SLE patients with impaired NET degradation could indicate renal involvement. NETs may be a therapeutic target in SLE. SLE patients with impaired NET degradation have higher anti-NET antibody titers and are more likely to develop lupus nephritis. These findings suggest that inefficient NET degradation contributes to SLE pathogenesis, particularly glomerulonephritis. The study highlights the role of NETs in autoimmunity and suggests that targeting NETs could be a potential therapeutic strategy for SLE.Systemic lupus erythematosus (SLE) is an autoimmune disease where patients produce autoantibodies against DNA, histones, and neutrophil proteins, leading to immune complex formation and lupus nephritis. Neutrophils release extracellular traps (NETs) during infections, which are made of DNA, histones, and neutrophil proteins. Timely degradation of NETs is crucial for tissue homeostasis and preventing self-antigen presentation. This study shows that serum DNase1 is essential for NET degradation. In SLE patients, impaired NET degradation is linked to kidney involvement. Two mechanisms cause this: (i) DNase1 inhibitors in SLE sera, and (ii) anti-NET antibodies that prevent DNase1 access to NETs. Impaired DNase1 function and poor NET degradation correlate with kidney involvement. Identification of SLE patients with impaired NET degradation could indicate renal involvement. NETs may be a therapeutic target in SLE. SLE patients with impaired NET degradation have higher anti-NET antibody titers and are more likely to develop lupus nephritis. These findings suggest that inefficient NET degradation contributes to SLE pathogenesis, particularly glomerulonephritis. The study highlights the role of NETs in autoimmunity and suggests that targeting NETs could be a potential therapeutic strategy for SLE.