Neutrophils impair B cell differentiation via mitochondrial and lipid metabolism in lupus.
Systemic lupus erythematosus (SLE) is characterised by aberrant neutrophil activation and pathogenic B-cell responses that drive organ damage, particularly in lupus nephritis (LN). Here, we identify neutrophil-derived mitochondrial DNA (mtDNA) as a metabolic driver of B-cell dysregulation in LN. Using single-cell transcriptomics of human blood and kidney tissue together with functional co-culture assays, we show that neutrophils from patients with active LN release extracellular traps enriched in mtDNA that induce mitochondrial oxidative stress in B cells. NET-derived mtDNA suppresses IL-10-producing regulatory B cells while promoting pro-inflammatory and plasmablast differentiation through nucleic acid-dependent signalling. Mechanistically, oxidative stress drives maladaptive NADPH utilisation, diverting NADPH from cholesterol biosynthesis toward antioxidant defence, resulting in altered lipid trafficking, mitochondrial dysfunction, and impaired regulatory B-cell differentiation. Consistent with this model, kidney B cells from patients with LN exhibit transcriptional signatures of disrupted redox and lipid metabolism, and NADPH deficiency is associated with reduced regulatory B-cell differentiation in humans. These findings identify a neutrophil-driven metabolic checkpoint that governs B-cell fate in lupus nephritis.