FNDC4 (fibronectin type III domain containing 4) is a secreted hepatokine and adipokine with pleiotropic functions in metabolic regulation, inflammation, and tissue protection. Primary Function: FNDC4 acts as an endocrine signaling molecule that promotes insulin sensitivity and glucose homeostasis primarily through its interaction with the adhesion GPCR GPR116 in white adipose tissue 1. It also reduces lipogenesis and promotes fat browning in visceral adipocytes while increasing mitochondrial biogenesis 2. Mechanism: The insulin-sensitizing effects are mediated via GPR116-dependent cAMP signaling 1. In cardiac tissue, FNDC4 alleviates ischemia/reperfusion injury through HIF1α-dependent cardiomyocyte survival and angiogenesis, as well as through ERK1/2-Nrf2-mediated antioxidative pathways 34. FNDC4 regulates neurogenesis by controlling the balance between glutamatergic and GABAergic neurons in developing brain tissue 5. Disease Relevance: FNDC4 levels are reduced in obesity and prediabetes, with genetic variants affecting FNDC4 splicing associated with alcohol use disorder risk and treatment outcomes 16. Unexpectedly, FNDC4 drives metastasis and immune evasion in pancreatic cancer by enhancing CCAR1/β-catenin signaling and promoting protumorigenic M2 macrophage polarization 7. Clinical Significance: Recombinant FNDC4 protein administration ameliorates cardiac injury and prediabetes in preclinical models 31, while FNDC4 inhibition combined with immunotherapy shows promise for pancreatic cancer treatment 7.