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Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review)

  • Authors:
    • Yan Xu
    • Xuesong Wang
    • Xiaolei Zhou
    • Lulu Peng
    • Jiayi Yuan
    • Yichi Zhang
    • Nan Wu
    • Junsong Ye
  • View Affiliations / Copyright

    Affiliations: Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, First Clinical College of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China, School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 152
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    Published online on: July 21, 2025
       https://doi.org/10.3892/ijmm.2025.5593
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Abstract

In the complex development of various diseases, nitric oxide‑mediated S‑nitrosylation is increasingly recognized for its distinct regulatory function. Recent research has advanced our knowledge of how this nitric oxide‑dependent modification is dynamically controlled under both physiological and pathological conditions. S‑nitrosylation plays a key role in regulating mitochondrial function, gene transcription, cellular homeostasis and metabolism and it is also involved in the pathogenesis of cardiovascular disorders, neurological conditions and cancer. The present review outlined the signaling pathways driven by nitric oxide and describes the formation, specificity and factors that influence S‑nitrosylation levels. It also compared the strengths and limitations of different detection methods for S‑nitrosation reactions. The present review discussed the cellular regulatory mechanisms affected by S‑nitrosylation to clarify how certain major diseases are connected to specific S‑nitrosylated proteins. These insights may guide the development of targeted repair strategies for malfunctioning proteins by focusing on defined S‑nitrosylation sites, offering theoretical support for disease intervention and treatment.
View Figures

Figure 1

NO-mediated 'classical' and
'non-classical' signaling pathways. (1) Classical signaling pathway: NO binds
to a specific R on the cell membrane and activates the GC system.
In the presence of Mg2+, GC converts GTP to cGMP. cGMP
activates inactive PKG, which influences effector proteins to
catalyze the phosphorylation of various intracellular proteins,
enabling the target cell to exert biological effects. (2) Non-classical signaling pathway: NO
interacts with specific cysteine sulfhydryl groups on target
proteins to form SNOs, which exert biological functions. SNOs can
be denitrosated and reduced to free sulfhydryl groups under TrxR
and GSNOR. Additionally, SNOs can transfer S-nitroso to cysteine
sulfhydryl groups of receptor proteins through Transnitrosase to
exert biological effects. NO, nitric oxide; R, receptor; GC,
guanylate cyclase; GTP, guanosine triphosphate; cGMP, cyclic
guanosine monophosphate; PKG, protein kinase G; SNOs,
S-nitrosothiols; TrxR, thioredoxin reductase; GSNOR,
S-nitrosoglutathione reductase.

Figure 2

Three S-nitrosylation reactions.
(1) NO reacts with O2
to form a series of nitrogen oxides. Subsequently,
N2O3 reacts with a protein thiol to produce
nitrite and a nitrosothiol. (2)
NO reacts with O2 to form NO2, which reacts
with a thiol to produce a thiol radical and nitrite. Then, NO
reacts with a thiol radical to form a nitrosothiol. (3) NO is oxidized by the transition
metal (such as Fe3+or Cu2+) to yield
nitrosonium. Nitrosonium then reacts with a thiol near the
catalytic center to form a nitrosothiol. NO, nitric oxide; RSH, a
protein thiol; R-SNO, a nitrosothiol.

Figure 3

Regulation of nitrosylated proteins
in cellular activities. (1)
Proteins regulating mitochondrial function: Drp1, Parkin, enzymes
in the tricarboxylic acid cycle, complexes I, II, III and IV in the
electron transport chain, ANT1, PINK1. (2) Proteins regulating gene
transcription: Nrf1, P53, HNF-1α, PPARγ, NF-κB, KLF. (3) Proteins regulating homeostasis:
NADPH oxidase, S100A8/A9, HSP90, CTSB. Drp1, Dynamin-related
protein 1; ANT1, adenine nucleotide translocator 1; PINK1,
PTEN-induced putative kinase 1; Nrf1, Nuclear respiratory factor 1;
HNF-1α, Hepatic Nuclear factor 1α; PPARγ, Peroxisome
proliferator-activated receptor γ; NF-κB, Nuclear factor kappa-B;
KLF, Kruppel-like factor; NADPH, Nicotinamide adenine dinucleotide
phosphate; HSP90, Heat shock protein 90; CTSB, Cathepsin B.

Figure 4

Regulatory functions of
S-nitrosylation in human diseases. (1) In the cardiovascular system, NO
affects specific cysteine sites of Plastin 3, Septin2 and PLS3
target proteins, leading to the development of AD and DD.
Conversely, the action of NO on cysteine sites of USP9X, AKT and
VASP target proteins can mitigate cardiovascular disorders such as
AS and ED. (2) In the nervous
system, the interaction of NO with cysteine sites of Caspase-3,
Parkin, Prx2 and Drp1 target proteins leads to the onset of glioma,
PD and AD. However, the action of NO on cysteine sites of ERK1 and
PTEN helps alleviate neurological disorders associated with glioma
and PD. (3) In tumor tissues,
the interaction of NO with specific cysteine sites of LTBP1,
RAB3GAP1, AGT and Ezrin target proteins induces CRC, PDAC, HCC and
NSCLC, while the effect of NO on cysteine sites of Fas, GAPDH and
ERK1 promotes apoptosis of cancer cells. (4) In metabolic diseases,
S-nitrosylation of INSR-β, IRS1 and AKT1 disrupts insulin
signaling; S-nitrosylation of PPARγ and PDE3B impairs adipocyte
function, leading to IR in adipocytes; and S-nitrosylation of SIRT1
sustains an inflammatory state, enhancing IR. PLS3, Plastin 3; AD,
Alzheimer's disease; DD, diastolic dysfunction; USP9X, ubiquitin
specific peptidase 9; AKT, protein kinase B; VASP,
vasodilator-stimulated phosphoprotein; AS, atherosclerosis; ED,
endothelial dysfunction; Prx2, peroxiredoxin 2; Drp1,
Dynamin-related protein 1; PD, Parkinson's disease; LTBP1, latent
transforming growth factor beta binding protein 1; RAB3GAP1, rab3
gtpase activating protein catalytic subunit 1; AGT,
angiotensinogen; CRC, colon cancer; PDAC, pancreatic ductal
adenocarcinoma; HCC, hepatocellular carcinoma; NSCLC, non-small
cell carcinoma; GAPDH, glyceraldehyde-3-phosphate dehydrogenase;
ERK1, extracellular signal-regulated kinase 1; INSR-β, Insulin
Receptor-β; IRS1, insulin receptor substrate 1; AKT1, RAC-alpha
serine/threonine-protein kinase; PPARγ, peroxisome
proliferator-activated receptor γ; PDE3B, phosphodiesterase 3B;
SIRT1, silent information regulator 1; IR, insulin resistance.
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Spandidos Publications style
Xu Y, Wang X, Zhou X, Peng L, Yuan J, Zhang Y, Wu N and Ye J: Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review). Int J Mol Med 56: 152, 2025.
APA
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y. ... Ye, J. (2025). Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review). International Journal of Molecular Medicine, 56, 152. https://doi.org/10.3892/ijmm.2025.5593
MLA
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y., Wu, N., Ye, J."Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review)". International Journal of Molecular Medicine 56.4 (2025): 152.
Chicago
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y., Wu, N., Ye, J."Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 152. https://doi.org/10.3892/ijmm.2025.5593
Copy and paste a formatted citation
x
Spandidos Publications style
Xu Y, Wang X, Zhou X, Peng L, Yuan J, Zhang Y, Wu N and Ye J: Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review). Int J Mol Med 56: 152, 2025.
APA
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y. ... Ye, J. (2025). Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review). International Journal of Molecular Medicine, 56, 152. https://doi.org/10.3892/ijmm.2025.5593
MLA
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y., Wu, N., Ye, J."Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review)". International Journal of Molecular Medicine 56.4 (2025): 152.
Chicago
Xu, Y., Wang, X., Zhou, X., Peng, L., Yuan, J., Zhang, Y., Wu, N., Ye, J."Nitric oxide‑mediated S‑Nitrosylation contributes to signaling transduction in human physiological and pathological status (Review)". International Journal of Molecular Medicine 56, no. 4 (2025): 152. https://doi.org/10.3892/ijmm.2025.5593
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