PNPLA3 is a membrane-associated acyltransferase that catalyzes CoA-dependent acylation of lysophosphatidic acid to phosphatidic acid, a critical precursor for triglyceride and glycerophospholipid synthesis 1. The protein also possesses lower-activity triacylglycerol lipase and transacylase activities involved in acyl-chain remodeling 23. PNPLA3 is the strongest genetic determinant of metabolic dysfunction-associated steatotic liver disease (MASLD), with the rs738409 G allele encoding I148M being most prevalent in populations at highest NAFLD risk 4. The I148M variant causes hepatic fat accumulation exceeding twofold in homozygotes and associates with liver inflammation and fibrosis across the full histological NAFLD spectrum 45. Mechanistically, I148M enhances NAFLD development through elevated IL-6/STAT3 signaling and NF-κB activity 6. In women, the I148M variant exhibits multiplicative interaction with estrogen receptor-α, explaining sex-dependent disease progression 7. Clinically, PNPLA3 genotyping improves cirrhosis risk stratification in NAFLD patients with indeterminate fibrosis markers 8. Therapeutic targeting via antisense oligonucleotides effectively reduces PNPLA3 expression and liver fat content, supporting precision medicine approaches for MASH 910.