G protein–coupled receptors (GPCRs) and proteases are deeply involved in many pathophysiological processes such as inflammation, cancer metastasis, and pain. They can both promote and, in some cases, resolve disease, emphasizing their prominent role as drug targets and/or biomarkers.

GPCRs are the largest superfamily of cell surface membrane receptors and are activated by a wide range of endogenous ligands, including ions, lipids, nucleotides, amines, small molecules, and peptides. Through the activation of different signaling cascades, GPCRs orchestrate complex biological processes such as proliferation, migration, differentiation, and cell metabolism, and are extensively involved in both health and disease.

Notably, GPCR signaling can involve proteases in several key ways to expand their signal transduction pathways. Proteases are proteolytic enzymes that catalyze the hydrolysis of peptide bonds, regulating a multitude of biological processes such as extracellular matrix (ECM) remodeling, digestion, and immune modulation. Functionally, they operate through various catalytic mechanisms (serine, cysteine, aspartic, and metalloprotease mechanisms) involving specific nucleophilic residues or cofactors to cleave target substrates with high precision. Their activity is tightly controlled by compartmentalization, zymogen activation, and endogenous inhibitors to prevent uncontrolled proteolysis. Nevertheless, GPCRs and proteases can activate each other through complex signaling. This type of cooperation provides a critical mechanism for integrating extracellular protease activity with cellular communication and has significant therapeutic potential in inflammation, hemostasis, and cancer.

This Research Topic aims to explore the multifaceted functions of GPCRs and proteases in pathophysiological processes, with a particular focus on the role of their interaction in the modulation of cell behavior and/or the microenvironment. We encourage submissions of any contribution type (e.g., original research articles, systematic or narrative reviews, mini-reviews, perspectives) aimed at unraveling the molecular mechanisms through which GPCRs and/or proteases modulate processes such as immune cell function, cell metabolism, tumor microenvironment dynamics, differentiation, and disease progression, as well as evaluating their potential as diagnostic biomarkers or therapeutic targets.

To advance our understanding of the complex mechanisms and roles of GPCRs, proteases, and their connections in translational medicine, we invite contributions addressing, but not limited to, the following themes:

Elucidation of signaling pathways related to GPCR and protease modulation in pathophysiological processes.

Characterization of proteases and/or GPCRs across different diseases, including their spatial and temporal distribution.

Investigation of the kinetic properties of distinct proteases using relevant substrates.

Modulation of protease activity within the cellular microenvironment through selective inhibitors.

Evaluation of proteases and/or GPCRs as diagnostic, prognostic, or therapeutic biomarkers in specific diseases, particularly in cancer.

Development and application of 3D cell and tissue models to better recapitulate the native microenvironment of proteases and GPCRs.

Are you interested in contributing a manuscript to this Research Topic?

Unraveling the GPCR–Protease Dialogue: Molecular Mechanisms and Therapeutic Implications in Pathophysiology