Neutrophil elastase (NE) and myeloperoxidase (MPO) regulate the formation of neutrophil extracellular traps (NETs). NE escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. MPO synergizes with NE to drive chromatin decondensation. NE is essential for initiating NET formation and is required for chromatin decondensation. NE degrades histones, particularly H4, to promote nuclear decondensation. MPO enhances NE-mediated decondensation and is involved in chromatin decondensation. NE and MPO translocate to the nucleus during NET formation, with NE playing a key role in histone degradation. NE knockout mice fail to form NETs in a pulmonary infection model, indicating that NE is critical for NET formation. NE is required for NET formation in vivo, as NE knockout mice do not form NETs in the lungs after Klebsiella pneumoniae infection. NE and MPO are stored in azurophilic granules and are released during NET formation. NE and MPO are involved in the release of granular proteins into the cytoplasm. NE and MPO work together to promote chromatin decondensation and NET formation. NE and MPO are essential for the formation of NETs, which are important for immune defense, sepsis, and autoimmunity. The study highlights the role of NE and MPO in the regulation of chromatin decondensation and NET formation.Neutrophil elastase (NE) and myeloperoxidase (MPO) regulate the formation of neutrophil extracellular traps (NETs). NE escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. MPO synergizes with NE to drive chromatin decondensation. NE is essential for initiating NET formation and is required for chromatin decondensation. NE degrades histones, particularly H4, to promote nuclear decondensation. MPO enhances NE-mediated decondensation and is involved in chromatin decondensation. NE and MPO translocate to the nucleus during NET formation, with NE playing a key role in histone degradation. NE knockout mice fail to form NETs in a pulmonary infection model, indicating that NE is critical for NET formation. NE is required for NET formation in vivo, as NE knockout mice do not form NETs in the lungs after Klebsiella pneumoniae infection. NE and MPO are stored in azurophilic granules and are released during NET formation. NE and MPO are involved in the release of granular proteins into the cytoplasm. NE and MPO work together to promote chromatin decondensation and NET formation. NE and MPO are essential for the formation of NETs, which are important for immune defense, sepsis, and autoimmunity. The study highlights the role of NE and MPO in the regulation of chromatin decondensation and NET formation.