Fifteen Years of PNPLA3: Transforming Hepatology Through Human Genetics

Steatotic liver disease (SLD), caused by excess lipid accumulation in hepatocytes, is now a leading global liver condition triggered by metabolic dysfunction, alcohol, toxins and heritable factors. The main genetic determinant is the common PNPLA3 p.I148M variant, which explains a substantial portion of SLD interindividual and interethnic variability, up to a quarter of liability to cirrhosis and liver cancer in the general population. Discovered in 2008 through genome-wide association studies, this variant increases the risk of liver steatosis, inflammation, fibrosis and the risk of complications as hepatocellular carcinoma. Carriers, particularly homozygotes, show higher susceptibility to liver damage, with the variant interacting with environmental factors such as increased adiposity, diet, insulin resistance and female sex. Experimental models indicate a complex mechanistic impact, involving lipid transfer and retinoid metabolism. Phase 1 clinical trials exploring PNPLA3 inhibitors, such as siRNA and antisense oligonucleotides, are promising, demonstrating up to 40% reductions in hepatic fat and inflammation in homozygous carriers. These advances suggest that targeting PNPLA3 can pave the way for precision medicine in hepatology. Overall, the discovery of PNPLA3's role has significantly enhanced understanding of liver steatosis, steatohepatitis and potential therapeutic interventions, highlighting its importance as a therapeutic target for SLD.