Hsd17b8, also known as estradiol 17-beta-dehydrogenase 8, is an enzyme that belongs to the 17β-hydroxysteroid dehydrogenases (HSD17B) family. It converts estradiol to estrone through its NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity [1]. It is also involved in acyl thioester metabolism, participating in pathways such as peroxisomal β-oxidation of fatty acids, mitochondrial oxidation of 3R-hydroxyacyl-groups, breakdown of isoleucine and fatty acid chain elongation in endoplasmic reticulum [2]. Hsd17b8 is a subunit of the heterotetrameric 3-ketoacyl-ACP reductase in mitochondrial fatty acid synthesis, assisting in the formation of the competent assembly [4].

In Caenorhabditis elegans, loss of the PTEN homolog daf-18 triggers cell division. Forward genetic screening identified F12E12.11 (ortholog of human HSD17B8) as being regulated by daf-18 and impacting cell proliferation independently of PTEN's typical phosphatase activity. PTEN physically interacts with HSD17B8, and inhibiting HSD17B8 suppresses the cell proliferation caused by PTEN failure. The reduction in estrone levels and accumulation of estradiol may arrest tumor cells in the G2/M phase of the cell cycle through MAPK/ERK [1]. In breast cancer, HSD17B8 is a protective gene. Higher expression of HSD17B8 is associated with a better prognosis for breast cancer patients [3]. In pathological cardiac hypertrophy, the expression of Hsd17b8 was down-regulated in male animals, suggesting a possible relation to the activation of the fetal gene expression program in pathological CH situations [5].

In conclusion, Hsd17b8 plays important roles in steroid metabolism, acyl thioester metabolism, and mitochondrial fatty acid synthesis. Studies using genetic models like in C. elegans have revealed its role in cell proliferation regulation related to PTEN failure. In disease conditions, it shows promise as a protective factor in breast cancer and is involved in the regulation of pathological cardiac hypertrophy, providing insights into potential therapeutic targets and disease mechanisms.