The GPR124‑Wnt‑PPARγ regulatory axis: Molecular mechanisms and therapeutic implications in chronic inflammatory...

G protein‑coupled receptor 124 (GPR124) and peroxisome proliferator‑activated receptor γ (PPARγ) constitute two mechanistically distinct signaling molecules that exhibit functional convergence through their opposing regulation of the canonical Wnt/β‑catenin pathway, thereby establishing a critical regulatory network governing inflammatory homeostasis and tissue repair responses. The present comprehensive review elucidates the molecular architecture and pathophysiological significance of the GPR124‑Wnt‑PPARγ regulatory axis, with particular emphasis on its therapeutic implications in chronic inflammatory diseases. GPR124, originally identified as an adhesion G protein‑coupled receptor essential for central nervous system angiogenesis and blood‑brain barrier integrity, functions as a context‑dependent co‑activator of Wnt7a/Wnt7b signaling. By contrast, PPARγ, a ligand‑activated nuclear receptor and master regulator of metabolism and inflammation, exerts potent antagonistic effects on Wnt/β‑catenin signaling through direct β‑catenin degradation mechanisms. The opposing regulation of Wnt signaling by these two receptors establishes a molecular framework that critically influences disease progression in atherosclerosis, diabetic complications, neuroinflammation and cancer‑associated inflammation, with its function being fine‑tuned by tissue‑specific expression patterns and diverse mechanisms. Understanding the GPR124‑Wnt‑PPARγ axis provides novel therapeutic opportunities for combination targeting strategies in chronic inflammatory conditions, where the balance between pro‑angiogenic Wnt activation and anti‑inflammatory PPARγ signaling determines disease outcomes. The present review examines the molecular architecture of GPR124‑PPARγ crosstalk, analyzes pathophysiological implications across multiple organ systems, and evaluates emerging therapeutic strategies for targeting this regulatory network in chronic inflammatory diseases.