iNOS in Macrophage Polarization: Pharmacological and Regulatory Insights

Macrophages play a central role in orchestrating inflammation and immune responses, with their polarization states (M1 or M2) exhibiting both pro- and anti-inflammatory, as well as anti-cancer functions. Inducible nitric oxide synthase (iNOS) plays a pivotal role in immune regulation through its impact on macrophage polarization. As a hallmark of M1 macrophages, iNOS drives pro-inflammatory responses, while its suppression favors anti-inflammatory M2 phenotypes. This dual role as both a biomarker and regulatory hub positions iNOS as a promising therapeutic target across diverse disease states. This review examines the roles of iNOS modulation in macrophage polarization across various disease models. Both synthetic and natural iNOS regulators have been shown to modulate iNOS activity, thereby reprogramming macrophages toward either inflammatory or reparative phenotypes. We categorize these regulators into those that directly inhibit enzymatic activity and those that indirectly modulate through signaling pathways. Additionally, recent preclinical and clinical studies on iNOS inhibitors are summarized, highlighting their therapeutic potential in inflammatory, metabolic, and oncologic diseases. Taken together, the evidence underscores the therapeutic relevance of iNOS regulation as a strategy to reprogram macrophage plasticity in disease-specific immune microenvironments.