Nitro-Fatty Acid Signaling in Inflammatory Responses

Nitro-fatty acids are endogenously generated electrophilic lipids formed by the reaction of nitric oxide–derived species with unsaturated fatty acids. These nitroalkene derivatives possess a conjugated nitro group that confers electrophilicity at the β-carbon, enabling reversible covalent modification of nucleophilic amino acid residues—most notably cysteine—within key regulatory proteins. Through Michael addition, nitro-fatty acids modulate diverse signalling pathways including inhibition of pro-inflammatory NF-κB activity, activation of antioxidant gene expression via the Keap1–Nrf2 axis, engagement of heat shock transcription factor responses and selective modulation of peroxisome proliferator-activated receptor γ (PPARγ). Collectively, these mechanisms suppress cytokine release, reduce expression of adhesion molecules and promote cytoprotection. The discovery of dietary and endogenous sources of nitro-fatty acids has spurred interest in their potential as therapeutic agents against inflammatory, fibrotic and metabolic disorders, underlining their global significance in health and disease.

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Nitro-Fatty Acid Signaling in Inflammatory Responses publication trend

The graph below shows the total number of articles in nitro-fatty acid signaling in inflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Nitro-fatty acids (NO₂-FAs): Endogenous electrophilic lipid mediators formed by nitration of unsaturated fatty acids.

Electrophilic nitroalkene: A chemical structure featuring a nitro group conjugated to a carbon–carbon double bond that undergoes Michael addition with nucleophiles.

Michael addition: A covalent reaction whereby an electrophile (e.g., nitroalkene) adds to a nucleophilic amino acid side chain in a protein.

NF-κB: A family of transcription factors central to pro-inflammatory gene expression, inhibited by nitroalkylation of its RelA/p65 subunit.

Keap1–Nrf2 pathway: A redox-sensitive system in which modification of Keap1 cysteines releases Nrf2 to activate antioxidant response element (ARE)-driven genes.

PPARγ: A nuclear receptor that regulates lipid metabolism and inflammation, selectively modulated by nitro-fatty acids acting as partial agonists.

References

1. Nitro-fatty acids: promising agents for the development of new cancer therapeutics. Trends in Pharmacological Sciences (2024).
2. Nitrated Fatty Acids: Endogenous Anti-inflammatory Signaling Mediators*. Journal of Biological Chemistry (2006).
3. Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism*. Journal of Biological Chemistry (2011).
4. Reversible Post-translational Modification of Proteins by Nitrated Fatty Acids in Vivo *. Journal of Biological Chemistry (2006).
5. Nitro-fatty Acid Reaction with Glutathione and Cysteine KINETIC ANALYSIS OF THIOL ALKYLATION BY A MICHAEL ADDITION REACTION* * This work was supported in part by National Institutes of Health Grants HL58115 and HL64937 (to B. A. F.) and AHA Grant 0450118Z (to B. P. B.), and a Department of Education GAANN (Graduate Assistance in Areas of National Need) award (to S. R. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.. Journal of Biological Chemistry (2007).
6. Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids SELECTIVE LIGAND ACTIVITY AND ANTI-DIABETIC SIGNALING ACTIONS*. Journal of Biological Chemistry (2010).
7. Olives and Olive Oil Are Sources of Electrophilic Fatty Acid Nitroalkenes. PLOS ONE (2014).