RNASE4 (ribonuclease A family member 4) is a secreted ribonuclease that functions as a multifaceted antimicrobial and tissue homeostasis protein. The enzyme cleaves RNA preferentially after uridine bases and demonstrates broad antimicrobial activity, particularly against uropathogenic E. coli and intestinal bacteria like Parasutterella 1. In the intestinal tract, RNASE4 is expressed by epithelial cells including Paneth and goblet cells, where it maintains gut microbiota homeostasis by modulating bacterial populations and enhancing IDO1-mediated metabolite production to reduce colitis susceptibility 1. Beyond its antimicrobial role, RNASE4 exhibits neuroprotective functions by promoting angiogenesis, neurogenesis, and neuronal survival under stress conditions 2. The protein shares promoter regions with angiogenin and demonstrates similar angiogenic capabilities 32. However, RNASE4 also contributes to pathological processes, promoting malignant progression and chemoresistance in glioblastoma through AXL/AKT and NF-κB signaling pathways 4, and serving as a biomarker for prostate cancer aggressiveness 5. Genetic variants in RNASE4 are associated with amyotrophic lateral sclerosis, with certain mutations causing loss of ribonucleolytic activity 67. Decreased RNASE4 levels correlate with inflammatory bowel disease, suggesting its potential as a diagnostic biomarker 1.