The role of free‐fatty acid receptors FFA1 and FFA4 in organ fibrosis

Abstract Fibrosis, a consequence of dysregulated wound healing underlying chronic diseases such as metabolic dysfunction‐associated steatohepatitis (MASH), inflammatory bowel disease (IBD), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (PF) and systemic sclerosis (SSc), accounts for nearly 45% of deaths in developed countries. Fibrosis is driven by persistent epithelial injury and aberrant communication among epithelial, mesenchymal, and immune cells, leading to fibroblast activation, myofibroblast accumulation, and excessive extracellular matrix (ECM) deposition. Despite its clinical significance, antifibrotic therapy remains largely limited to pirfenidone and nintedanib for PF and resmetirom for MASH. The continued failure of many candidates in clinical development highlights the persistent unmet need for more effective antifibrotic approaches. FFA1 (GPR40) and FFA4 (GPR120) are free‐fatty acid receptors (FFAR) that sense medium‐ and long‐chain fatty acids, primarily coupling to Gα q/11 and β‐arrestin signalling pathways to regulate diverse physiological processes. Although these FFAR have been extensively investigated in the context of metabolic disorders, emerging evidence indicates that FFA1 and FFA4 also play critical roles in the pathophysiology of fibrosis across multiple organs. This review highlights the roles of FFA1 and FFA4 in mitigating fibrosis, either directly or indirectly, across various organs, including the liver, kidney, lung, heart, and peritoneum, as well as in disorders associated with fibrosis‐related injuries.