The dual role of formyl peptide receptor 1 (FPR1) in gastrointestinal inflammation and carcinogenesis: mechanisms and therapeutic implications.

Formyl Peptide Receptor 1 (FPR1), a Class A G protein-coupled receptor (GPCR), is a context-dependent regulator at the interface of gastrointestinal inflammation and cancer. Recent structural insights have revealed its functional diversity. FPR1 responds to diverse exogenous and endogenous ligands, activating downstream mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), and protein kinase B (Akt) pathways. These signals can either exacerbate neutrophil-driven tissue damage or promote inflammation resolution and epithelial repair. This functional duality extends to cancer, where FPR1 signaling can foster tumor progression by shaping the immunosuppressive microenvironment and driving angiogenesis, or conversely, suppress tumor growth by activating anti-tumor immunity and pro-resolving programs. The receptor's association with disease prognosis and the existence of functional single nucleotide polymorphisms (SNPs) underscores it is a target for therapeutic intervention. However, the event and tissue specific signaling outputs and dualistic nature of FPR1 present significant challenges for pharmacological intervention. This review integrates current knowledge on FPR1's structural biology and ligand-biased signaling, analyzing its dual roles in inflammatory bowel disease (IBD), gastric cancer (GC), colorectal cancer (CRC). We analyze the mechanisms underlying the FPR1-facilitated "inflammation-to-cancer" transition and explore emerging therapeutic strategies, including structure-based rational design of small-molecule modulators, development of biased ligands to steer signaling toward beneficial outcomes, and the potential of combination therapies with chemotherapy or immunotherapy. By bridging mechanistic insights with pharmacological innovation, targeting FPR1 holds considerable promise for pioneering novel precision medicine approaches for digestive system diseases.