ARRDC4 (arrestin domain containing 4) is a multifunctional adapter protein with critical roles in metabolism, innate immunity, and disease pathogenesis. The protein functions as a metabolic regulator, where high glucose promotes MondoA-mediated transcriptional upregulation of ARRDC4, which then increases lysosomal GLUT1 trafficking and blocks glucose transport in cardiomyocytes, forming a negative feedback mechanism 1. ARRDC4 deletion improves cardiac reserve and exercise capacity in diabetes by augmenting tissue glucose transport and mitochondrial respiration 1. In innate immunity, ARRDC4 senses influenza A virus infection by interacting with viral PA protein and enhances glycolysis through binding to PFKM, promoting fructose-1,6-bisphosphate production that subsequently enhances NF-κB- and IRF7-mediated antiviral responses 2. Additionally, ARRDC4 promotes K63 polyubiquitination of MDA5 through TRIM65 interaction, activating downstream innate signaling and proinflammatory cytokine transcription during enterovirus 71 infection 3. Clinically, ARRDC4 shows differential expression patterns in various diseases: it is upregulated in diabetic complications and correlates with immune cell infiltration in type 2 diabetes 4, while being suppressed in colorectal cancer where its downregulation promotes metastasis through ZEB1 signaling 5. The protein also responds to intracellular acidification during cellular senescence, potentially contributing to senescence-associated inflammatory responses 6.