Emerging GPCR Agonist-Based Therapies to Trigger the Resolution of Inflammation

The long-lasting paradigm that inflammation resolves through a passive decline of pro-inflammatory signals has been fundamentally revised by extensive research demonstrating that the resolution of inflammation is an active, programmed, and tightly regulated process driven by a temporally coordinated sequence of molecular and cellular events for restoring tissue homeostasis. Under physiological conditions, specialized lipid pro-resolving mediators (SPMs), as well as some pro-resolving proteins and peptides, initiate the resolution of inflammation process by halting pro-inflammatory immune cell recruitment, clearance of effector cells and cellular inflammatory debris, tissue repair, and restoration of local immunity. Clinical and experimental observations indicate that failure to activate this endogenous pro-resolving program or alteration of SPM synthesis leads to persistent inflammatory activity, contributing to chronic diseases such as arthritis, Alzheimer's disease, cancer, and inflammatory bowel disorders through excessive neutrophil infiltration, impaired efferocytosis, and unresolved tissue damage. Advances in the understanding of SPMs, their biology, and their mechanisms have driven the development of new therapeutic molecules mimicking the activity of endogenous pro-resolving lipids or pro-resolutive proteins and derivatives. Multiple classes of molecules, including stabilized lipid analogs, peptides, and agonist antibodies, have shown promising preclinical activity, particularly through ChemR23 (gene CMKLR1) and formyl peptide receptor 2 (FPR2) targeting. Ongoing and completed phase I/II clinical trials report encouraging results in conditions such as eczema and ocular diseases, with favorable safety profiles. Unlike traditional anti-inflammatory strategies, these approaches engage a natural physiological program rather than inhibiting or depleting inflammatory pathways, aiming to establish long-term tissue homeostasis without compromising the immune system. Emerging pro-resolutive G protein-coupled receptor (GPCR) therapies are designed for enhanced target specificity, biodistribution, and specific pro-resolutive signaling for sustained efficacy. Targeting pro-resolving GPCRs holds strong potential to redefine the treatment of inflammatory diseases by promoting the active reinstatement of immune balance and homeostasis.