PNPLA4 is an X-linked phospholipase and triacylglycerol lipase with multiple enzymatic activities critical for lipid homeostasis. Primary functions include abundant triacylglycerol lipase activity, retinyl ester hydrolysis, fatty acid transfer from triglycerides to retinol, and phospholipase A2 activity 1. PNPLA4 regulates glycerophospholipid turnover in human cells; knockdown reduced phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine turnover by 30-50% and inhibited G0/G1 to S cell cycle progression 1. At the molecular level, PNPLA4 functions in primary cilia formation and mitochondrial-mediated ATP production through energy metabolism regulation 2. Disease relevance spans multiple systems. PNPLA4 mutations cause mitochondrial respiratory chain complex deficiencies 3. Copy number variations and duplications at Xp22.31 containing PNPLA4 associate with heterotaxy and congenital heart disease, with PNPLA4 expression critical in lateral plate mesoderm and neural crest lineages during left/right patterning and cardiomyocyte differentiation 2. X-linked intellectual disability involves PNPLA4 deletions, supported by high brain transcript expression 4. PNPLA4 also associates with cardiac arrhythmias and gastrointestinal disorders in Xp22.31 deletion carriers 5, and represents a component of mitochondrial lipid metabolism gene signatures prognostic for colorectal cancer 6. Altered PNPLA4 expression occurs during multiple myeloma progression 7.