Cytosolic fMet-Protein Synthesis as Source of Endogenous Ligands for Formyl Peptide Receptors

Formyl peptides, exemplified by the synthetic tripeptide formyl-Met-Leu-Phe (fMLF), are well-established ligands for formyl peptide receptors (FPRs), central to neutrophil chemotaxis, and innate immune signaling. Traditionally attributed to bacterial and mitochondrial origins, these peptides are now proposed to arise from an additional, stress-inducible source within the eukaryotic cytosol. Recent findings suggest that under specific stress conditions, eukaryotic translation can initiate with formylmethionine (fMet), producing fMet-bearing nascent chains that are processed by the fMet/N-degron and fMet-mediated ribosome quality control (fMet-RQC) pathways. These proteostatic mechanisms may generate short, structurally diverse formyl peptides with the potential to function as endogenous FPR ligands. By introducing cytosolic proteostasis as a hypothetical source of formyl peptides, this perspective expands the landscape of formyl peptide biology and opens new directions for investigating their roles in immune regulation under stress and disease.