Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Sep 13;14(18):6465.
doi: 10.3390/jcm14186465.

Targeting Mitochondrial Reactive Oxygen Species: JP4-039's Potential as a Cardiovascular Therapeutic

Keertana Yalamanchili  1   2 , Mark Broadwin  1   2 , Dwight D Harris  1   2 , Rayane B Teixeira  1   2 , Frank W Sellke  1   2 , Peter Wipf  3   4 , M Ruhul Abid  1   2
Affiliations
Review

Targeting Mitochondrial Reactive Oxygen Species: JP4-039's Potential as a Cardiovascular Therapeutic

Keertana Yalamanchili et al. J Clin Med. .

Abstract

JP4-039, a mitochondrial-targeted nitroxide, has emerged as a promising candidate in addressing the intricate interplay of reactive oxygen species (ROS) in cardiovascular disease (CVD). Given the substantial mortality and economic burden associated with CVD globally, novel therapeutic strategies targeting oxidative stress hold significant promise. The pathophysiology of CVD encompasses multifaceted mechanisms, including endothelial dysfunction, inflammation, and oxidative stress, where dysregulated ROS levels play a pivotal role. JP4-039, by selectively targeting mitochondrial ROS, offers a targeted approach to mitigate oxidative stress-induced damage in cardiovascular tissue. Current research elucidates the molecular mechanisms underlying JP4-039's antioxidant properties, including its ability to scavenge superoxide radical anions and mitigate oxidative chain reactions within mitochondria. Moreover, preclinical studies highlight JP4-039's efficacy in ameliorating CVD-related pathologies, including atherosclerosis and cardiac hypertrophy, through its antioxidative and anti-inflammatory effects. Future milestones in JP4-039 research involve optimizing its pharmacokinetic (PK) properties and exploring potential synergistic effects with existing cardiovascular therapies, followed by advancing into clinical trials.

Keywords: JP4-039; cardiovascular disease; mitochondrial antioxidants; reactive oxygen species.

PubMed Disclaimer

Conflict of interest statement

Peter Wipf is a named inventor on patents held by the University of Pittsburgh covering JP4-039 composition and use. The JP4-039 patent is identified as WO 2010/009389A1; Use of targeted nitroxide agents in preventing, mitigating and treating radiation injury, by Wipf, P.; Belikova, N. A.; Jiang, J.; Greenberger, J. S.; Pierce, J. G.; Epperly, M. Publication Date: 21 January 2010. M.R.A. is the co-founder of a non-profit organization Health and Education for All (HAEFA) USA, and has served as a consultant for ARI Science, MA, and XM Therapeutics, Providence, RI, which do not have any conflicts with the current study. The other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Sources of reactive oxygen species (ROS) in the cell, including the mitochondrial electron transport chain (ETC), peroxisomes, endoplasmic reticulum, and immune responses. These endogenous pathways, along with exogenous sources such as UV and ionizing radiation, and exposure to pollutants and pesticides, contribute to the redox imbalance implicated in cardiovascular disease. Created with BioRender.com. ROS, reactive oxygen species; ETC, electron transport chain; ER, endoplasmic reticulum; O2, molecular oxygen; ·O2−, superoxide anion; H2O2, hydrogen peroxide; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); RAC, Ras-related C3 Botulinum Toxin Substrate; p47(phox), Neutrophil Cytosolic Factor 1; p67(phox), Neutrophil Cytosolic Factor 2; and p40(phox), Neutrophil Cytosolic Factor 4.
Figure 2
Figure 2
Molecular structure of JP4-039 (PubChem Compound ID: 70894087), where gray atoms represent carbon, white atoms represent hydrogen, red atoms represent oxygen, and blue atoms represent nitrogen. This 3D molecular model was generated and visualized using MolView v2.4 software.
Figure 3
Figure 3
MAPK (mitogen-activated protein kinase) signaling pathways (p38, ERK1/2, and JNK) in cardiovascular disease. These cascades regulate inflammation, apoptosis, and remodeling, contributing to hypertension, atherosclerosis, and myocardial infarction. JP4-039’s ability to modulate the phosphorylation of these kinases suggests potential cardioprotective effects. Created with BioRender.com. MAP2Ks, mitogen-activated protein kinase kinases; MAPK, mitogen-activated protein kinase; p38, p38 mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinases 1 and 2; JNK, c-Jun N-terminal Kinase; ATP, adenosine triphosphate; ADP, adenosine diphosphate; and P, phosphate group.
See this image and copyright information in PMC

References

    1. Brown J.C., Gerhardt T.E., Kwon E. StatPearls. StatPearls Publishing; Petersburg, FL, USA: 2023. Risk Factors for Coronary Artery Disease. - PubMed
    1. Deaton C., Froelicher E.S., Wu L.H., Ho C., Shishani K., Jaarsma T. The global burden of cardiovascular disease. Eur. J. Cardiovasc. Nurs. 2011;10((Suppl. 2)):S5–S13. doi: 10.1016/S1474-5151(11)00111-3. - DOI - PubMed
    1. Nichols G.A., Bell T.J., Pedula K.L., O’Keeffe-Rosetti M. Medical care costs among patients with established cardiovascular disease. Am. J. Manag. Care. 2010;16:e86–e93. - PubMed
    1. Olvera Lopez E., Ballard B.D., Jan A. StatPearls. StatPearls Publishing; Petersburg, FL, USA: 2023. Cardiovascular Disease. - PubMed
    1. Frąk W., Wojtasińska A., Lisińska W., Młynarska E., Franczyk B., Rysz J. Pathophysiology of Cardiovascular Diseases: New Insights into Molecular Mechanisms of Atherosclerosis, Arterial Hypertension, and Coronary Artery Disease. Biomedicines. 2022;10:1938. doi: 10.3390/biomedicines10081938. - DOI - PMC - PubMed

LinkOut - more resources