HSD17B6 is a NAD-dependent oxidoreductase with broad substrate specificity that catalyzes oxidative and reductive reactions on steroids and retinoids 1. The enzyme converts 5-alpha-androstan-3-alpha,17-beta-diol to androsterone and estradiol to estrone, demonstrating 17-beta-hydroxysteroid dehydrogenase activity 2. Beyond steroid metabolism, HSD17B6 has retinol dehydrogenase activity toward all-trans-retinol and acts on both C-19 and C-21 3-alpha-hydroxysteroids 1. Mechanism: HSD17B6 plays a novel non-enzymatic role in glucose homeostasis by binding to the SREBP/SCAP/INSIG complex and inhibiting SREBP maturation, independent of its steroid oxidase activity 1. This SREBP inhibition reduces hepatic de novo lipogenesis and improves glucose tolerance. Disease relevance: Low HSD17B6 expression correlates with poorer overall and progression-free survival in hepatocellular carcinoma patients and associates with reduced tumor-infiltrating immune cells 3. HSD17B6 polymorphisms are associated with polycystic ovary syndrome phenotypes including altered body mass index and androgen status 4. Additionally, parabens and benzophenone UV-filters inhibit HSD17B6, potentially reducing DHT synthesis through the backdoor androgen pathway 2. Clinical significance: Hepatic HSD17B6 expression improves glucose tolerance and reduces type 2 diabetes development in diet-induced obese mice 1, positioning it as a potential therapeutic target for metabolic disorders. However, HSD17B6 deletion does not affect diet-induced fatty liver disease development 5.