17-beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1)

17-beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the steroidogenic pathway, primarily responsible for the conversion of the weak estrogen estrone (E1) into the potent estradiol (E2) using NADPH as a cofactor [1, 2]. It also plays a role in the inactivation of the potent androgen dihydrotestosterone (DHT) by converting it into 3β-androstanediol [1, 14]. While naturally expressed in the placenta and ovarian granulosa cells, 17β-HSD1 is frequently overexpressed in peripheral tissues such as the breast and endometrium, where it drives the progression of hormone-dependent diseases by increasing local estrogen concentrations [1, 8]. Consequently, it is a major therapeutic target for conditions like estrogen-dependent breast cancer, endometriosis, and endometrial hyperplasia [4, 6, 12]. Unlike aromatase inhibitors, which cause systemic estrogen depletion, 17β-HSD1 inhibitors aim to reduce estrogen production specifically within diseased tissues, potentially offering a more targeted therapeutic approach with fewer side effects [12]. Several inhibitors, such as linustedastat and various experimental steroidal and non-steroidal compounds, have been developed to block its activity and are being evaluated for their efficacy in treating estrogen-sensitive malignancies and gynecological disorders [3, 12, 15].

Other names

HSD17B1Estradiol 17-beta-dehydrogenase 120 alpha-hydroxysteroid dehydrogenaseE2DHPlacental 17-beta-hydroxysteroid dehydrogenaseShort chain dehydrogenase/reductase family 28C member 1SDR28C1EDH17B2EDHB17

Competitive inhibition of the enzyme's active site to prevent the NADPH-dependent reduction of the weak estrogen estrone into the potent estradiol, thereby lowering local estrogenic signaling in target tissues.