INTRODUCTION: Neutrophil extracellular traps (NETs) contribute to inflammation and are implicated in autoimmune diseases; however, their role in IgA nephropathy (IgAN) remains unclear. This study aimed to investigate the involvement of NETosis in IgAN and its impact on renal injury and mesangial cell function, utilizing patient samples, mouse models, and in vitro assays. METHODS: RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from IgAN patients to identify differentially expressed genes (DEGs) and NETosis-related pathways. An IgAN mouse model was established using bovine serum albumin, carbon tetrachloride, and lipopolysaccharide. Mice were treated with the peptidyl arginine deiminase-4 inhibitor GSK484 to evaluate the effects of NETosis inhibition. In vitro assays assessed the impact of NETosis on mesangial cells. RESULTS: RNA sequencing identified 905 DEGs in IgAN patients, with significant enrichment in neutrophil and NETosis pathways. Serum levels of NETosis markers - citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase - were elevated in IgAN patients, with CitH3 levels correlating with Gd-IgA1. Inhibiting NETosis with GSK484 reduced CitH3 levels in IgAN mice and improved clinical outcomes, including decreased proteinuria and increased serum albumin. Histological analysis revealed reduced mesangial proliferation. In vitro, NETosis enhanced tumor necrosis factor-α (TNF-α) release from mesangial cells, an effect that was mitigated by GSK484. RNA-seq analysis of kidneys from GSK484-treated IgAN mice also revealed significant alterations in the PPAR signaling pathway. Additionally, TNF-α treatment of mesangial cells resulted in reduced PPARα expression, suggesting that NETosis may modulate this pathway through the release of TNF-α by mesangial cells. CONCLUSION: Our findings demonstrate that NETosis is upregulated in IgAN and plays a key role in its pathogenesis by promoting inflammatory cytokine release. Inhibition of NETosis improves both clinical and pathological outcomes, highlighting its potential as a therapeutic approach for managing IgAN.