Aldo-keto reductase family 1 member C3 (AKR1C3) (AKR1C3)

Aldo-keto reductase family 1 member C3 (AKR1C3), also known as Type 5 17-β-hydroxysteroid dehydrogenase (17β-HSD5), is a key steroidogenic enzyme responsible for the local production of potent androgens and estrogens [1, 12]. It primarily catalyzes the reduction of 4-androstenedione to testosterone and estrone to 17β-estradiol, facilitating hormone-dependent signaling in peripheral tissues [4, 8]. Beyond steroid metabolism, AKR1C3 also functions as a prostaglandin F synthase, converting PGD2 to 11β-PGF2α, which promotes cell proliferation and survival through the activation of MAPK and NF-κB pathways [2, 15]. The enzyme is highly overexpressed in various malignancies, most notably castration-resistant prostate cancer (CRPC) and estrogen-receptor-positive breast cancer, where it drives intratumoral hormone synthesis and mediates resistance to standard therapies like abiraterone and enzalutamide [3, 9, 13]. Targeting AKR1C3 with selective inhibitors such as ASP9521 or utilizing it to activate prodrugs like OBI-3424 represents a promising therapeutic strategy for advanced cancers [13, 15, 18]. However, therapeutic development has faced challenges regarding isoform selectivity, as non-selective inhibition of the closely related AKR1D1 enzyme has been associated with hepatotoxicity in clinical studies [2, 15].

Other names

Type 5 17-beta-hydroxysteroid dehydrogenase17-beta-HSD517-beta-hydroxysteroid dehydrogenase type 5HSD17B5Prostaglandin F synthase (PGFS)3-alpha-hydroxysteroid dehydrogenase type 2Indomethacin-binding protein

Inhibition of the enzyme-catalyzed conversion of weak steroid precursors into potent androgens and estrogens, and modulation of prostaglandin-mediated proliferative signaling.