Arrdc4, or arrestin domain-containing protein 4, is a member of the α-arrestin protein family. It has essential functions in regulating nutrient transporter trafficking, extracellular vesicle biogenesis, and is involved in various biological pathways related to metabolism, cell-to-cell communication, and innate immunity [1,2,4]. Genetic models, especially knockout mouse models, have been crucial in understanding its in vivo functions.

In knockout mouse models, Arrdc4-KO mice show mild fasting hypoglycemia, increased myocardial glucose uptake and glycogen storage, and improved energy homeostasis during ischemia, protecting cardiomyocytes against myocardial infarction. This indicates its role in regulating cardiac metabolism through interaction with GLUT1, driving glucose-deprivation-induced endoplasmic reticulum stress and cardiomyocyte death [1]. In diabetes, systemic deletion of Arrdc4 improves cardiac reserve and exercise capacity by augmenting tissue glucose transport and mitochondrial respiration [3]. Also, sperm from Arrdc4-/-mice fail to acquire proper motility and fertilization capabilities due to reduced extracellular vesicle production by epididymal epithelial cells, highlighting its importance in sperm maturation [2].

In conclusion, Arrdc4 plays diverse and significant roles in biological processes. Model-based research, particularly the use of Arrdc4-KO mouse models, has revealed its functions in cardiac metabolism, diabetes-related complications, and sperm maturation, providing potential therapeutic insights for ischemic heart disease and diabetic cardiomyopathy [1,3].