biostudies-literatureTong SChapman UniversityNational Cancer InstituteNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS1701https://www.ebi.ac.uk/biostudies/studies/S-EPMC8807785biostudies-literatureUnknown12(1)Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated siScientific reportsInhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS).PMC8807785R01 GM049725Faculty Opportunity GrantR35 GM131788K08CA179084K08 CA1790841R35GM131788-01Silverman RBTong SPatel ACinelli MAHuang HEl-Sayed NSYang SfalseInhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS).Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated si2022-01-01T00:00:00Z2022 Feb2025-04-05T13:57:53.367Z2025-04-05T13:57:53.367ZS-EPMC88077853510591510.1038/s41598-022-05394-6