Fndc4, Fibronectin type III domain-containing protein 4, contains a type III FN domain which can bind to DNA, heparin, or cell surface, functioning as a signal transmitter after cleavage and secretion as sFNDC4 [2]. It is involved in multiple biological processes such as inflammation, metabolism, and angiogenesis, and plays a significant role in various diseases [2].

In cardiac I/R injury, cardiac-specific FNDC4 overexpression promotes, while knockdown inhibits cardiomyocyte survival and angiogenesis in male mice, indicating its protective role through regulating HIF1α-dependent pathways [1]. In metabolic dysfunction-associated steatotic liver disease, FNDC4-knockdown in HepG2 hepatocytes increases apoptotic cell death, and FNDC4 treatment blunts inflammatory cell death, suggesting it functions as a hepatocyte survival factor via AMPKα [3]. In pre-diabetic mice, lowering of FNDC4 leads to prediabetes, and supplementation with sFNDC4 improves glucose tolerance, showing its role in glucose homeostasis [4].

In conclusion, Fndc4 plays crucial roles in multiple disease conditions including cardiac I/R injury, metabolic-related liver diseases, and diabetes-related conditions. Gene knockout or knockdown models in mice have been instrumental in revealing its functions in promoting cardiomyocyte survival, angiogenesis, hepatocyte survival, and regulating glucose homeostasis, providing potential therapeutic targets for these diseases.