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The AOPP-cNOS relay: A Redox-Metabolic pathway in the lung-brain axis of pulmonary hypertension and neurovascular injury.

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Title: The AOPP-cNOS relay: A Redox-Metabolic pathway in the lung-brain axis of pulmonary hypertension and neurovascular injury.
Authors: Lee SS; College of Medicine, Konyang University, Daejeon, Republic of Korea. Electronic address: 24851506@konyang.ac.kr., Moon JH; College of Medicine, Konyang University, Daejeon, Republic of Korea., Lee SH; College of Medicine, Konyang University, Daejeon, Republic of Korea.
Source: Free radical biology & medicine [Free Radic Biol Med] 2026 Feb 01; Vol. 243, pp. 367-380. Date of Electronic Publication: 2025 Nov 20.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE
Imprint Name(s): Publication: Tarrytown, NY : Elsevier Science
Original Publication: New York : Pergamon, c1987-
MeSH Terms: Hypertension, Pulmonary*/metabolism , Hypertension, Pulmonary*/pathology , Hypertension, Pulmonary*/drug therapy , Lung*/metabolism , Lung*/pathology , Advanced Oxidation Protein Products*/metabolism , Nitric Oxide Synthase*/metabolism, Brain/metabolism ; Brain/pathology ; Receptor for Advanced Glycation End Products/metabolism ; Reactive Oxygen Species/metabolism ; Humans ; Oxidation-Reduction ; Animals ; Oxidative Stress ; Signal Transduction ; Metabolic Networks and Pathways
Abstract: Advanced oxidation protein products (AOPPs) are increasingly recognized not only as markers of oxidative damage but also as active mediators of redox imbalance. In parallel, uncoupling of constitutive nitric oxide synthases (cNOS) represents a central pathological switch linking oxidative stress to vascular dysfunction. Here, we propose the AOPP-cNOS axis as a mechanistic and therapeutic framework bridging lung inflammation, pulmonary hypertension, and neurovascular injury. We critically evaluate how AOPPs amplify myeloperoxidase (MPO)- and RAGE-driven signaling, propagate reactive nitrogen/oxygen species, and promote cNOS uncoupling through BH4 oxidation and ADMA accumulation. This axis connects chronic lung inflammation with systemic endothelial dysfunction, advancing to blood-brain barrier breakdown and neurovascular injury. From a translational perspective, we highlight drug-targetable nodes: (i) MPO inhibitors and RAGE antagonists to suppress upstream AOPP generation, (ii) BH4 salvage and arginase blockade to restore NOS coupling, and (iii) PDE5 inhibitors to preserve downstream NO-cGMP signaling. We also propose a biomarker panel (AOPPs, 3-chlorotyrosine, BH4/BH2 ratio, ADMA, serum neurofilament light chain, BBB imaging) that may enable patient stratification and precision monitoring. By integrating mechanistic insights with therapeutic opportunities, the AOPP-cNOS framework positions oxidative protein products as both predictive biomarkers and actionable drug targets, offering a novel pathway for pharmacological intervention in chronic lung-brain comorbidities.
(Copyright © 2025 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Advanced Oxidation Protein Products (AOPPs); Lung–brain axis; Nitric oxide synthase uncoupling; Protein oxidation; Pulmonary hypertension; Redox biomarkers; Translational free radical biology
Substance Nomenclature: 0 (Advanced Oxidation Protein Products)
EC 1.14.13.39 (Nitric Oxide Synthase)
0 (Receptor for Advanced Glycation End Products)
0 (Reactive Oxygen Species)
Entry Date(s): Date Created: 20251122 Date Completed: 20260110 Latest Revision: 20260110
Update Code: 20260130
DOI: 10.1016/j.freeradbiomed.2025.11.042
PMID: 41274320
Database: MEDLINE
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  Data: <searchLink fieldCode="AU" term="%22Lee+SS%22">Lee SS</searchLink>; College of Medicine, Konyang University, Daejeon, Republic of Korea. Electronic address: 24851506@konyang.ac.kr.<br /><searchLink fieldCode="AU" term="%22Moon+JH%22">Moon JH</searchLink>; College of Medicine, Konyang University, Daejeon, Republic of Korea.<br /><searchLink fieldCode="AU" term="%22Lee+SH%22">Lee SH</searchLink>; College of Medicine, Konyang University, Daejeon, Republic of Korea.
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  Data: <searchLink fieldCode="JN" term="%228709159%22">Free radical biology & medicine</searchLink> [Free Radic Biol Med] 2026 Feb 01; Vol. 243, pp. 367-380. <i>Date of Electronic Publication: </i>2025 Nov 20.
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  Data: <i>Publication</i>: Tarrytown, NY : Elsevier Science<br /><i>Original Publication</i>: New York : Pergamon, c1987-
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Advanced oxidation protein products (AOPPs) are increasingly recognized not only as markers of oxidative damage but also as active mediators of redox imbalance. In parallel, uncoupling of constitutive nitric oxide synthases (cNOS) represents a central pathological switch linking oxidative stress to vascular dysfunction. Here, we propose the AOPP-cNOS axis as a mechanistic and therapeutic framework bridging lung inflammation, pulmonary hypertension, and neurovascular injury. We critically evaluate how AOPPs amplify myeloperoxidase (MPO)- and RAGE-driven signaling, propagate reactive nitrogen/oxygen species, and promote cNOS uncoupling through BH<subscript>4</subscript> oxidation and ADMA accumulation. This axis connects chronic lung inflammation with systemic endothelial dysfunction, advancing to blood-brain barrier breakdown and neurovascular injury. From a translational perspective, we highlight drug-targetable nodes: (i) MPO inhibitors and RAGE antagonists to suppress upstream AOPP generation, (ii) BH<subscript>4</subscript> salvage and arginase blockade to restore NOS coupling, and (iii) PDE5 inhibitors to preserve downstream NO-cGMP signaling. We also propose a biomarker panel (AOPPs, 3-chlorotyrosine, BH<subscript>4</subscript>/BH<subscript>2</subscript> ratio, ADMA, serum neurofilament light chain, BBB imaging) that may enable patient stratification and precision monitoring. By integrating mechanistic insights with therapeutic opportunities, the AOPP-cNOS framework positions oxidative protein products as both predictive biomarkers and actionable drug targets, offering a novel pathway for pharmacological intervention in chronic lung-brain comorbidities.<br /> (Copyright © 2025 Elsevier Inc. All rights reserved.)
– Name: Abstract
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Advanced Oxidation Protein Products (AOPPs); Lung–brain axis; Nitric oxide synthase uncoupling; Protein oxidation; Pulmonary hypertension; Redox biomarkers; Translational free radical biology
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  Data: 0 (Advanced Oxidation Protein Products)<br />EC 1.14.13.39 (Nitric Oxide Synthase)<br />0 (Receptor for Advanced Glycation End Products)<br />0 (Reactive Oxygen Species)
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        Value: 10.1016/j.freeradbiomed.2025.11.042
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        Text: English
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        StartPage: 367
    Subjects:
      – SubjectFull: Brain metabolism
        Type: general
      – SubjectFull: Brain pathology
        Type: general
      – SubjectFull: Receptor for Advanced Glycation End Products metabolism
        Type: general
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      – SubjectFull: Humans
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      – SubjectFull: Oxidation-Reduction
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      – SubjectFull: Metabolic Networks and Pathways
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      – SubjectFull: Hypertension, Pulmonary metabolism
        Type: general
      – SubjectFull: Hypertension, Pulmonary pathology
        Type: general
      – SubjectFull: Hypertension, Pulmonary drug therapy
        Type: general
      – SubjectFull: Lung metabolism
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      – SubjectFull: Lung pathology
        Type: general
      – SubjectFull: Advanced Oxidation Protein Products metabolism
        Type: general
      – SubjectFull: Nitric Oxide Synthase metabolism
        Type: general
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      – TitleFull: The AOPP-cNOS relay: A Redox-Metabolic pathway in the lung-brain axis of pulmonary hypertension and neurovascular injury.
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              Text: 2026 Feb 01
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