Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) (HSD17B13)

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) is a liver-specific enzyme localized to lipid droplets and belongs to the short-chain dehydrogenase/reductase (SDR) superfamily (UniProt Q7Z5P4). It has emerged as a high-priority therapeutic target for chronic liver diseases following genomic studies that identified a protective loss-of-function splice variant, rs72613567 (Abul-Husn et al., NEJM 2018). This genetic variant is associated with a significantly reduced risk of progressing from simple steatosis to more severe conditions such as metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Although its exact physiological substrates are still being characterized, evidence suggests it plays a role in the metabolism of lipids or retinoids within the liver (Ma et al., Hepatology 2019). Current drug development efforts, including RNA interference (RNAi) therapies like ARO-HSD and ALN-HSD, aim to mimic this genetic protection by silencing the HSD17B13 gene in hepatocytes (Arrowhead Pharmaceuticals; Alnylam Pharmaceuticals). Small molecule inhibitors are also being explored to block the enzyme's catalytic activity. The target is particularly attractive because the naturally occurring human knockout phenotype appears to be healthy, suggesting a favorable safety profile for therapeutic inhibition.

Other names

Short-chain dehydrogenase/reductase 9SCDR917-beta-hydroxysteroid dehydrogenase 13HSD17B13

RNA interference (RNAi) mediated gene silencing or small molecule inhibition of enzymatic activity to mimic the protective effect of naturally occurring loss-of-function variants.