Evidence map›Paper›PMID 42248132›Full record

ReviewRedox biology2026

Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.

Leandro L Coutinho, Erika M Palmieri, Lisa A Ridnour, Robert Y S Cheng, William F Heinz, Stephen K Anderson, Timothy R Billiar, Jenny Chang, Stephen J Lockett, M Cristina Rangel and 3 more

Abstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in Redox biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Leandro L CoutinhoCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Erika M PalmieriCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Lisa A RidnourCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Robert Y S ChengCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
William F HeinzOptical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Stephen K AndersonCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Timothy R BilliarDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jenny ChangHouston Methodist Neal Cancer Center, Weill Cornell Medical College, Houston Methodist Hospital, Houston, TX, USA.
Stephen J LockettOptical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
M Cristina RangelCenter for Translational Research in Oncology, ICESP/HC, Faculdade de Medicina da Universidade de São Paulo and Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, SP, 01246-000, Brazil.
Douglas D ThomasDepartment of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA. Electronic address: ddthomas@uic.edu.
Daniel W McVicarCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. Electronic address: mcvicard@mail.nih.gov.
David A WinkCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. Electronic address: wink@mail.nih.gov.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2) lie at a critical intersection between inflammation, metabolism, and oncogenic signaling, where they cooperatively promote and establish a Nitric Oxide (NO)-driven Warburg phenotype in advanced cancers. Early work in macrophages established NOS2-derived NO as both a signaling molecule and metabolic stressor that inhibits oxidative phosphorylation (OXPHOS) by targeting iron-sulfur enzymes and respiratory complexes, forcing neighboring cells to rewire metabolism. In human tumors, sustained NOS2 expression in cancer cells and tumor-associated macrophages (TAMs) enforces a Warburg-like state characterized by high glycolytic flux, glutamine dependence, and enhanced NADPH production, supporting proliferation, biosynthesis, and resistance to oxidative stress. At nitrosative-signaling concentrations (≈100-500 nM), NO breaks carbon entry into the TCA cycle at aconitase and pyruvate dehydrogenase, progressively disables dehydrogenase complexes containing dihydrolipoamide dehydrogenase (DLD) and electron-transport complexes (ETCs), and activates hypoxia-inducible factor 1-alpha (HIF-1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase (ERK)/pyruvate kinase M2 (PKM2)/c-Myc signaling axis, nuclear factor erythroid 2-related factor 2 (Nrf2), and transforming growth factor Beta (TGF-β)/SMAD pathways. These biochemical and signaling effects convert transient glycolytic adaptation into chemically enforced dependency, further stabilized by metabolite-driven inhibition of ten-eleven translocation (TET) and Jumonji demethylases, creating an "epigenetic lock" that maintains oncogenic transcriptional programs. NOS2 and COX2 form a reciprocal feed-forward circuit in which NO, prostaglandin E2 (PGE

Indexed as

Cyclooxygenase 2NeoplasmsNitric OxideNitric Oxide Synthase Type IIWarburg Effect, OncologicAnimalsHumansMetabolic ReprogrammingSignal TransductionCyclooxygenase 2Nitric OxideNitric Oxide Synthase Type IINOS2 protein, humanCOX2-PGE(2) signalingMetabolic reprogrammingNitric oxide synthase 2 (NOS2)Tumor microenvironment (TME)Warburg effect

Identifiers

PMID42248132
PMCPMC13259629

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.