NOS2 encodes inducible nitric oxide synthase, which catalyzes the production of nitric oxide (NO), a critical signaling molecule with pleiotropic functions in immunity and inflammation. In macrophages and other immune cells, NOS2-derived NO mediates tumoricidal and bactericidal activities and regulates inflammatory responses by enhancing production of pro-inflammatory mediators such as IL-6 and IL-8. NOS2 also possesses nitrosylase activity, mediating cysteine S-nitrosylation of cytoplasmic proteins including PTGS2/COX2 and components of the GAIT complex, which modulates inflammatory responses and gene expression. NOS2 plays complex roles in cancer biology. While classically recognized as part of the antitumor immune response, NOS2 expression in cancer cells often predicts poor outcomes 1. Recent evidence demonstrates that NOS2 expression and NO signaling promote malignant transformation through epigenetic mechanisms, including degradation of DNMT1 and resulting DNA hypomethylation, retrotransposon activation, and genomic instability 2. In psoriasis, a recent study proposes that IL-17–induced NOS2 expression is fine-tuned post-translationally to generate marginal NO levels that promote keratinocyte proliferation and inflammation, with therapeutic benefit observed in both NOS2-knockout and NO-donor–treated models 3. In Th17 cell development, physiological NO concentrations support differentiation and stability of human Th17 cells through cGMP-dependent signaling 4. NOS2 genetic variants have shown associations with type 2 diabetes and diabetic nephropathy in the Chinese Han population 5. Clinical-stage NOS2 inhibitors including GW-274150 and tilarginine acetate are under development for inflammatory and malignant diseases.