RNASE6 is a cationic antimicrobial ribonuclease belonging to the RNaseA superfamily that preferentially cleaves RNA at pyrimidine bases 1. The protein possesses a unique dual catalytic center architecture with two catalytic triads (His15/His122/Lys38 and His36/His39/Lys87) that facilitates endonuclease-type cleavage of polymeric substrates 1. RNASE6 demonstrates potent bactericidal activity against both Gram-positive and Gram-negative bacteria, including uropathogenic E. coli, P. aeruginosa, and S. aureus, through bacterial cell agglutination and membrane permeabilization mechanisms independent of its RNase catalytic activity 2. In vivo studies using RNASE6 transgenic mice revealed protective effects during experimental urinary tract infection, with monocytes and macrophages serving as primary cellular sources 3. Beyond antimicrobial function, RNASE6 acts as an immune regulatory RNA-binding protein that promotes M1 macrophage polarization, inhibits melanoma metastasis, and correlates with improved immunotherapy response 4. A common polymorphism (rs1045922) affecting the R66Q position influences antimicrobial efficacy through altered lipopolysaccharide binding 5. RNASE6 expression also modifies APOE-ε4 effects on cognition, implicating neuroinflammatory pathways in Alzheimer's disease 6. These findings establish RNASE6 as a multifunctional innate immune effector with clinical relevance to infection, cancer, and neurodegeneration.