Bioactive Compounds as Modulators of N-Formyl Peptide Signaling in Chronic Diseases

Abstract

In physiological situations involving cell damage, molecules derived from mitochondria or bacteria are produced. These molecules are known as N-formyl peptides and are detected by formyl peptide receptors (FPRs), which stimulate immune cells to migrate to the specific site of injury or infection. Despite their initially beneficial effects on health, N-formyl peptides also contribute to the development or exacerbation of chronic non-communicable diseases. Therefore, understanding the metabolic pathways related to the involvement of N-formyl peptides and FPRs may increase our ability to regulate immune responses and precisely target FPRs with personalized strategies, offering a promising approach for the treatment of specific diseases. In this way, bioactive compounds in food may influence N-formyl peptides, interacting with the receptors either competitively or by inhibiting them, which affects the inflammatory response and oxidative reactions of cells. This review examines the pathways associated with forming N-formyl peptides, the activation of FPRs, and the roles of bioactive compounds in regulating N-formyl peptides.

Keywords: N-formyl peptides; bioactive compounds; diet; formyl peptide receptors; non-communicable disease.

Figure 1

N-Formylmethionine (fMet) synthesis. fMet is the first amino acid in the synthesis of all bacterial proteins. The enzyme formyltransferase (FMT) and its cofactor 10-formyltetrahydrofolate (10-fTHF) originate from fMet, and the complex mRNA and fMet-tRNA initiate protein synthesis. Due to their bacterial ancestry, mitochondria are also a source of N-formyl peptides. Created by BioRender.com.

Figure 2

Activation of the FPR by formyl peptides from mitochondria or bacteria triggers both physiological and pathological processes. Abbreviations: fMLP, N-formyl-methionyl-leucyl-phenylalanine; fMIFL, N-formyl-methionine-isoleucine-phenylalanine-leucine; fMIVIL, N-formyl-methionine-isoleucine-valine-isoleucine-leucine; PSMα, modulins of the alpha type; fMLPK, N-formyl-Met-Leu-Phe-Lys; fMLPIK, N-formyl-Met-Leu-Phe-Ile-Lys; MCT-2, mitocryptide-2; fMMYALF, N-formyl-methionine-methionine-tyrosine-alanine-leucine-phenylalanine; fMYFINILTL, N-formyl-methionine-tyrosine-phenylalanine-isoleucine-asparagine-isoleucine-leucine-threonine-leucine; fMLKLIV, N-formyl-methionine-leucine-lysine-leucine-isoleucine-valine. Created by BioRender.com.

Figure 3

Impacts of mitochondria and bacteria N-formyl peptides on the progression of various pathological conditions. N-formyl peptides such as fMLP, as well as those derived from mitochondrial proteins, bacterial sources, and PSMα peptides, function as immunomodulatory agents. These peptides are involved in the pathogenesis of multiple diseases, including diabetes mellitus, kidney disorders, cancer, cardiovascular diseases (CVDs), and neurodegenerative diseases. The illustration highlights key pathological mechanisms associated with N-formyl peptide activity, including inflammation, oxidative stress, the progression of cardiovascular disease (CVD), tumor development, podocyte injury, and neuroinflammation. Created by BioRender.com.

Figure 4

Dose-dependent effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) on intestinal homeostasis. At physiological concentrations, fMLP promotes superoxide production, modulates inflammation, maintains epithelial integrity, stimulates cell proliferation, supports mucosal repair, reinforces colonic barrier function, and facilitates the elimination of pathobionts—processes that collectively contribute to intestinal health. In contrast, elevated concentrations of fMLP are associated with adverse outcomes, including the depletion of microenvironmental oxygen, overgrowth of anaerobic bacterial consortia, mucosal damage, colonic erosion, ulcer formation, and inflammation. Created by BioRender.com.

Figure 5

Bioactive compounds as adjuvant treatment for modulation of N-formyl peptide signaling pathways and their receptors. Some bioactive compounds in food may inhibit N-formyl peptides and their receptors, thereby reducing the proliferation of H. pylori and the production of reactive oxygen species (ROS) and anion superoxide, as well as mitigating inflammation and reducing the intracellular calcium concentration. Created by BioRender.com.