PM20D1 is a secreted peptidase M20 domain-containing enzyme that functions as a bidirectional N-fatty acyl amino acid (NAA) synthase/hydrolase, regulating tissue and circulating NAA levels 1. The enzyme condenses free fatty acids and amino acids to generate NAAs, which stimulate oxidative metabolism and increase energy expenditure through UCP1-independent mitochondrial uncoupling 2. PM20D1 circulates in tight association with lipoproteins that co-activate its enzymatic activity, while serum albumin serves as a physiologic NAA carrier regulating the bioavailability of thermogenic lipids 3. Genetically, natural variants in the PM20D1 promoter and downstream regions significantly influence gene expression across tissues including brown adipose tissue, muscle, and liver, impacting cold tolerance and body mass 4, 2. Enhanced PM20D1 expression promotes muscle mass and function, making it a promising pharmacological target for sarcopenia 5. Clinically, PM20D1 demonstrates neuroprotective roles in neurodegenerative diseases. The PM20D1-NADA pathway protects against Parkinson's disease by inhibiting α-synuclein aggregation and reducing neuronal degeneration 6. PM20D1 is also associated with Alzheimer's disease risk through genetic-epigenetic interactions, with PM20D1 upregulation providing neuroprotection 7, 8. Additionally, reduced serum PM20D1 levels are associated with poor prognosis in idiopathic pulmonary arterial hypertension patients 9.