ROS signaling in innate immunity via oxidative protein modifications. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in innate immune function, including respiratory bursts and inflammasome activation. ROS are short-lived intermediates that regulate cellular signaling and proliferation, with their subcellular location influencing their function. NADPH oxidase generates superoxide anion, which is converted to hydrogen peroxide (H2O2) and used by myeloperoxidase to produce hypochlorous acid (HOCl), mediating pathogen killing. H2O2 modulates redox-responsive transcription factors like NF-κB, NRF2, and HIF-1, mediating redox-based epigenetic modifications. Immune cell survival and function depend on intracellular and extracellular levels of ROS/RNS. This review focuses on redox factors involved in immune response activation and the role of ROS in oxidative protein modifications in macrophage polarization and neutrophil function. ROS are produced in various cellular compartments, including the cytoplasm, endoplasmic reticulum, mitochondria, and peroxisomes. ROS regulate cellular homeostasis and signaling events, contributing to disease pathology. In infectious inflammation, ROS regulate adhesion molecules, enabling leukocyte migration to the injury site. In sterile inflammation, ROS contribute to macrophage polarization and tissue repair. ROS are also involved in metabolic reprogramming of immune cells, influencing their function and response to pathogens. ROS are produced by various sources, including NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS), and mitochondrial electron transport chain. NOX-derived ROS are involved in angiogenesis and neutrophil extracellular trap formation. ROS also regulate protein oxidation, affecting cellular function and signaling. Oxidative modifications of proteins, such as sulfenic, sulfinic, and sulfonic acids, can alter protein structure and function, influencing immune responses. ROS can also mediate nitrosylation, leading to the formation of 3-nitrotyrosine, which is associated with inflammation and disease progression. ROS signaling is essential for immune cell activation, including macrophage and neutrophil functions. ROS regulate the metabolic reprogramming of macrophages, influencing their polarization and function. In M1 macrophages, aerobic glycolysis and HIF1α activation are crucial for inflammatory responses. In M2 macrophages, oxidative metabolism and fatty acid oxidation support anti-inflammatory functions. ROS also regulate neutrophil activation, including phagocytosis, oxidative burst, and extracellular trap formation. Neutrophil functions are influenced by cellular redox status, with ROS levels determining pathogen sensing and immune response activation. ROS-mediated epigenetic modifications, such as DNA demethylation and histone modifications, influence macrophage differentiation and function. ROS can also affect histone deacetylases (HDROS signaling in innate immunity via oxidative protein modifications. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in innate immune function, including respiratory bursts and inflammasome activation. ROS are short-lived intermediates that regulate cellular signaling and proliferation, with their subcellular location influencing their function. NADPH oxidase generates superoxide anion, which is converted to hydrogen peroxide (H2O2) and used by myeloperoxidase to produce hypochlorous acid (HOCl), mediating pathogen killing. H2O2 modulates redox-responsive transcription factors like NF-κB, NRF2, and HIF-1, mediating redox-based epigenetic modifications. Immune cell survival and function depend on intracellular and extracellular levels of ROS/RNS. This review focuses on redox factors involved in immune response activation and the role of ROS in oxidative protein modifications in macrophage polarization and neutrophil function. ROS are produced in various cellular compartments, including the cytoplasm, endoplasmic reticulum, mitochondria, and peroxisomes. ROS regulate cellular homeostasis and signaling events, contributing to disease pathology. In infectious inflammation, ROS regulate adhesion molecules, enabling leukocyte migration to the injury site. In sterile inflammation, ROS contribute to macrophage polarization and tissue repair. ROS are also involved in metabolic reprogramming of immune cells, influencing their function and response to pathogens. ROS are produced by various sources, including NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS), and mitochondrial electron transport chain. NOX-derived ROS are involved in angiogenesis and neutrophil extracellular trap formation. ROS also regulate protein oxidation, affecting cellular function and signaling. Oxidative modifications of proteins, such as sulfenic, sulfinic, and sulfonic acids, can alter protein structure and function, influencing immune responses. ROS can also mediate nitrosylation, leading to the formation of 3-nitrotyrosine, which is associated with inflammation and disease progression. ROS signaling is essential for immune cell activation, including macrophage and neutrophil functions. ROS regulate the metabolic reprogramming of macrophages, influencing their polarization and function. In M1 macrophages, aerobic glycolysis and HIF1α activation are crucial for inflammatory responses. In M2 macrophages, oxidative metabolism and fatty acid oxidation support anti-inflammatory functions. ROS also regulate neutrophil activation, including phagocytosis, oxidative burst, and extracellular trap formation. Neutrophil functions are influenced by cellular redox status, with ROS levels determining pathogen sensing and immune response activation. ROS-mediated epigenetic modifications, such as DNA demethylation and histone modifications, influence macrophage differentiation and function. ROS can also affect histone deacetylases (HD