The roles of free-fatty acid receptors in the pathophysiology of renal disorders

Kidney diseases represent one of the most prevalent and rapidly growing global health burdens, with rising mortality linked to both acute kidney injury and chronic kidney disease (CKD). Despite the increasing incidence of CKD affecting 8%-16% of the world's population, therapeutic options remain limited, largely because of an incomplete understanding of underlying pathophysiology and the lack of reliable biomarkers. Recent evidence highlights that free-fatty acids (FFA), particularly short-chain and long-chain fatty acids, are beneficial modulators of renal health, associated with reduced CKD risk and slower kidney function decline. Although effects of FFA have historically been linked to their intracellular activity, they can also engage a family of cell-surface G protein-coupled FFA receptors (FFAR), including FFARs FFA2/GPR43 and FFA3/GPR41, which are activated by short-chain fatty acids, and FFA1/GPR40 and FFA4/GPR120, which are agonized by long-chain fatty acids. This review summarizes current knowledge of FFAR-mediated mechanisms in acute kidney injury, CKD, and associated renal pathologies, emphasizing their potential as therapeutic targets to improve kidney outcomes. We also discuss the therapeutic relevance of dietary FFA related to these FFAR in relation to renal disease. SIGNIFICANCE STATEMENT: Fatty acid sensing G protein-coupled receptors have emerged as important regulators of renal inflammation, fibrosis, and tubular survival across acute and chronic models of kidney injury. This review synthesizes current evidence for short- and long-chain free-fatty acid receptors in kidney disease, highlights translational relevance, and outlines challenges that must be addressed to advance free-fatty acid receptor-targeted therapies.