LACC1 (laccase domain containing 1) is a purine nucleoside enzyme that serves as a critical regulator of innate immunity and metabolic homeostasis in macrophages. The protein catalyzes the phosphorolysis of adenosine, guanosine, and inosine nucleosides, yielding D-ribose 1-phosphate and free bases, and also demonstrates adenosine deaminase activity 1. LACC1 modulates purine nucleotide metabolism to regulate the metabolic function and bioenergetic state of macrophages through a purine nucleotide cycle that prevents cytoplasmic acidification 1. Additionally, LACC1 converts L-citrulline to L-ornithine and isocyanic acid, bridging NOS2 and polyamine immunometabolism to support anti-inflammatory and antibacterial macrophage functions 2. The protein associates with the NOD2-signaling complex and promotes optimal NOD2-induced signaling, cytokine secretion, and bacterial clearance 3. LACC1 also localizes to the endoplasmic reticulum upon pattern recognition receptor stimulation and promotes the unfolded protein response 4. Loss-of-function variants in LACC1 are associated with juvenile arthritis and inflammatory bowel disease 56. Disease-risk variants, particularly the Val254 variant, demonstrate reduced PRR-induced outcomes including decreased mitochondrial ROS production, signaling, and bacterial clearance compared to the protective Ile254 variant 3.