Phytochemicals as Modulators of NETosis: A Comprehensive Review on Their Mechanisms and Therapeutic Potential

Medicinal plants have a longstanding history in the treatment of various diseases, including infectious and inflammatory disorders. These therapeutic effects are attributed to the presence of bioactive compounds. Among these, phytochemicals, particularly polyphenols such as curcumin, luteolin, resveratrol, alkaloids, and terpenoids, play a significant role as a secondary metabolites with potent NETosis-modulating properties. Phytochemicals include a wide range of bioactive substances with various therapeutic properties, including anti-inflammatory, antibacterial, anticancer, anti-metastatic, and antioxidant effects. These compounds specifically target NETosis in inflammatory and autoimmune disorders such as rheumatoid arthritis, lupus erythematosus, psoriasis, and cancer. In such conditions, unregulated inflammatory responses lead to complications and disease progression. Innate immunity and neutrophils are recognized as the primary constituents of the immune response. NETosis is a process associated with neutrophils in the inflammatory response, which is initiated to eliminate pathogens; however, as it is dysregulated, it results in tissue damage. This process is initiated in order to eliminate external factors and modulate inflammatory pathways. However, excessive activation of NETosis leads to tissue damage and exacerbates inflammation. The phytochemicals discussed herein modulate NETosis through distinct mechanisms, including inhibiting or reducing key mediators such as MPO, NE, and ROS. This study provides the first comprehensive review systematically evaluating the active phytochemicals effect in the treatment of various diseases, with a special focus on their NETosis-modulating effects. We highlight their specific mechanism of action against NETotic pathways and clinical potential as targeted therapies for NET-driven disease.