NPL (N-acetylneuraminate pyruvate lyase) is a cytosolic enzyme that catalyzes the cleavage of N-acetylneuraminic acid (sialic acid) into pyruvate and N-acetylmannosamine via a Schiff base intermediate, preventing sialic acid recycling to the cell surface 1. NPL participates in the degradation pathway of N-glycolylneuraminic acid (Neu5Gc), which humans cannot synthesize but must degrade when acquired from dietary sources 1. NPL expression is widespread across tissues including liver, kidney, placenta, and peripheral blood leukocytes 2. Functionally, NPL is essential for skeletal muscle integrity and regeneration; deleterious NPL variants cause elevated free sialic acid accumulation, reduced muscle force and endurance, impaired myofiber regeneration following injury, and mitochondrial dysfunction with aberrant sialylation of key proteins 3. NPL activity increases after fasting, injury, and in muscle dystrophy contexts, establishing it as a general marker of muscle damage 3. Clinically, NPL deficiency manifests as skeletal myopathy and cardiac edema in humans and model organisms, with N-acetylmannosamine supplementation demonstrating rescue of myopathy and mitochondrial abnormalities in mouse models 3, suggesting a potential therapeutic avenue for affected patients.