{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nInducible nitric oxide synthase (NOS2) is a tightly regulated enzyme that catalyzes the production of nitric oxide (NO), a highly diffusible free‐radical messenger with multifaceted roles in innate host defense and immunomodulation. NOS2‐derived NO exerts microbicidal, antiviral, and antiparasitic effects and is induced in response to proinflammatory cytokines and microbial signals. In several studies, genetic polymorphisms in the NOS2 promoter region have been linked to enhanced basal NO production and protection against severe infections such as malaria and tuberculosis, while tightly controlled NOS2 expression underpins rapid, effective innate immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, NOS2 exerts a paradoxical influence on tumor biology. Elevated NOS2 expression and subsequent NO production have been implicated in promoting tumor angiogenesis, metastasis, and chemoresistance, yet in some settings NO also mediates cytotoxicity. Numerous observations across diverse malignancies—including colorectal, breast, glioma, melanoma, and cutaneous as well as head and neck carcinomas—associate high NOS2 levels with aggressive tumor behavior, activation of oncogenic signaling pathways (for example, via EGFR and mTOR‐linked mechanisms), and poor clinical outcomes. Moreover, genome‐wide association studies have identified NOS2 as a susceptibility locus in dermatologic disorders such as psoriasis, underscoring its involvement in both neoplastic and chronic inflammatory processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNOS2 is also central to neuroinflammatory and neurodegenerative processes. Studies in models of HIV‐associated dementia, Alzheimer’s disease, and Parkinson’s disease demonstrate that aberrant induction of NOS2 in glial cells and neurons contributes to nitrosative stress, neuronal injury, and consequent cognitive and motor deficits. In cultured astrocytes, specific cytokine combinations robustly stimulate NOS2 expression, further linking chronic neuroinflammation to pathological outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe expression and activity of NOS2 are governed by complex regulatory networks that include transcriptional control, post‐translational modifications, and precise domain movements required for electron transfer. Multiple studies have demonstrated that NOS2 protein levels are modulated via ubiquitination and transcriptional repression (for example, through NF‑κB–repressing factors), while its catalytic efficiency depends on the proper orientation of bound cofactors. Such mechanistic insights underscore the importance of epigenetic and structural determinants in fine‐tuning NOS2 activity and NO production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant NOS2 activity is implicated in diverse non‐neoplastic conditions spanning vascular and reproductive abnormalities, pulmonary disorders, and severe inflammatory syndromes. In the vasculature and placenta, NOS2‐derived NO influences endothelial function and trophoblast motility, affecting aortic homeostasis and contributing to disorders such as preeclampsia. In parallel, altered NOS2 expression in the lung is reflected by changes in exhaled NO levels in chronic obstructive pulmonary disease, while dysregulated NO signaling has been linked to catastrophic skin injury in toxic epidermal necrolysis and to systemic inflammatory conditions including chronic fatigue syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "42", "end_ref": "50"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J F Kun, B Mordmüller, D J Perkins, et al. 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