Narrative Review of the FNDC5 Gene and Irisin: Structural, Phylogenetic, and Functional Aspects

The FNDC5 (Fibronectin Type III Domain Containing 5) gene encodes a transmembrane precursor protein that, upon proteolytic cleavage, releases irisin—a pleiotropic myokine originally described as a regulator of energy metabolism and white adipose tissue browning. Subsequent research has expanded the FNDC5/irisin axis to include critical roles in glycemic homeostasis, musculoskeletal anabolism, neuroprotection, and the modulation of immune, hepatic, renal, and tumor microenvironments. This narrative review comprehensively examines the discovery, structural biology (including irisin's unique homodimerization), complex proteolytic processing, and physiological functions of FNDC5. Furthermore, it explores the evolutionary relationship with its closest paralog, FNDC4, highlighting FNDC4's complementary role as a systemic anti-inflammatory and metabolic mediator. Phylogenetic mapping reveals deep evolutionary conservation of this signaling pathway, evidenced by a functional homolog in invertebrates (Drosophila melanogaster), gene duplication (FNDC5a/FNDC5b) in teleost fish, and functional presence in birds and reptiles, contrasted with an apparent secondary gene loss in amphibians. In mammals, the gene exhibits high structural conservation despite lineage-specific variations, such as the controversial translation initiation site mutation (ATG→ATA) in hominids, which has recently been contextualized by the discovery of an upstream conserved start codon. We conclude that the FNDC5/irisin system is an ancient, highly conserved, and functionally diverse molecular network. Addressing remaining gaps regarding the precise mechanisms of its proteolytic cleavage, physiological regulation in understudied taxa, and specific receptor interactions remains a critical frontier for future research.