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Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions, including phagocytosis, production of reactive oxygen and halogen species, degranulation, and NETosis (formation of neutrophil extracellular traps (NETs). NETs, which contain antimicrobial compounds such as myeloperoxidase (MPO), represent a strategy to combat infection. However, excessive production of NETs promotes thrombosis, diabetes mellitus, and other diseases. Therefore, investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders. Here, we identified a novel NETosis inducer, human serum albumin (HSA) modified by the MPO product hypochlorous acid (HSA _HOCl), whose accumulation in vivo was correlated with inflammatory processes. Using human blood neutrophils, we investigated HSA _HOCl-induced NETosis and detected NET formation by flow cytometry. The results showed that the mechanism of HSA _HOCl-induced NETosis involved MPO, NADPH oxidase and phosphatidylinositol 3-kinases, and that HSA _HOCl activated a reactive oxygen species-dependent suicidal type of NETosis. Moreover, HSA _HOCl-induced NETosis was inhibited by an anti-HSA _HOCl monoclonal antibody. Thus, our findings may facilitate the development of strategies to modulate NETosis in inflammation correlated with elevated MPO activity.