PNPLA2 (patatin-like phospholipase domain containing 2), also known as adipose triglyceride lipase (ATGL), is the rate-limiting enzyme for triglyceride hydrolysis in adipocytes and non-adipocytes 1. The protein catalyzes the initial step in lipolysis by hydrolyzing triacylglycerols to release fatty acids from lipid droplets, preferentially acting at the sn-2 position 21. PNPLA2 functions through dynamic protein-protein interactions on lipid droplet surfaces, where it is activated by its co-activator ABHD5 and regulated by negative regulators including G0S2 and PLIN1 1. Beyond lipolysis, PNPLA2 participates in lipophagy, the selective autophagy of lipid droplets, and has been identified as part of the lipid droplet proteome in macrophage foam cells 3. Disease-wise, PNPLA2 mutations cause neutral lipid storage disease with myopathy, and recent studies demonstrate its involvement in arrhythmogenic cardiomyopathy, where AAV9-mediated gene therapy successfully prevents and rescues cardiac dysfunction in mouse models 4. Additionally, genome-wide association studies have identified PNPLA2 variants associated with nonalcoholic fatty liver disease risk 5. Therapeutically, ATGL inhibition shows promise for treating metabolic dysfunction-associated steatohepatitis by attenuating PPARα signaling and promoting hydrophilic bile acid composition 6.