Argininosuccinate lyase (ASL) catalyzes the fourth step of the urea cycle, cleaving argininosuccinate into fumarate and arginine 1. This reaction is essential for hepatic nitrogen detoxification and de novo arginine synthesis in non-hepatic tissues 1. ASL functions as a critical regulator of intracellular and extracellular arginine pools and forms tissue-specific multiprotein complexes with other urea cycle enzymes and nitric oxide synthases, channeling locally synthesized arginine to nitric oxide production 1. Recent evidence demonstrates that cardiac ASL activation through time-restricted feeding protects against heart failure by upregulating the cardiac urea cycle and generating urea cycle-derived nitric oxide 2. ASL deficiency (ASLD) is the second most common urea cycle disorder, affecting approximately 1 in 70,000 live births 1. Clinically, ASLD manifests as either severe neonatal-onset hyperammonemia or late-onset episodic hyperammonemia with long-term complications including liver dysfunction, neurocognitive deficits, and hypertension 1. Notably, some patients develop severe neurological disease without experiencing hyperammonemia, suggesting ASL has functions beyond ureagenesis 1. Over 134 different ASL mutations have been identified across diverse populations 3. Current treatment includes protein restriction and arginine supplementation, with emerging approaches using CRISPR base editing showing promise for restoring urea cycle function 4.