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Estradiol 17-beta-dehydrogenase 8 (HSD17B8)

Target: HSD17B8
Molecular classification: Enzyme, Short-chain dehydrogenase/reductase (SDR) family, Oxidoreductase, Mitochondrial fatty acid synthase subunit

Overview

Estradiol 17-beta-dehydrogenase 8 (HSD17B8) is an NAD-dependent enzyme that belongs to the short-chain dehydrogenase/reductase (SDR) family and functions both in steroid hormone metabolism and mitochondrial fatty acid biosynthesis. It primarily catalyzes the oxidation of biologically active 17β-hydroxy-steroids (such as estradiol and testosterone) into weaker 17-ketosteroids (such as estrone and androstenedione), thereby regulating the local bioavailability of estrogens and androgens. In the context of cancer biology, particularly estrogen receptor-positive breast cancer, HSD17B8 modulates cell proliferation by adjusting the estradiol–estrone balance and interacting with the PTEN tumor suppressor, impacting the MAPK/ERK signaling pathway and the cell cycle. The enzyme also serves as a critical scaffold for mitochondrial fatty acid synthase complex assembly and activity.

Other names: HSD17B8Hydroxysteroid 17-beta dehydrogenase 8(3R)-3-hydroxyacyl-CoA dehydrogenaseFABGLHKE6RING2SDR30C117-beta-HSD 8KAR alpha subunitKe6D6S2245EH2-KE63-ketoacyl-[acyl-carrier-protein] reductase alpha subunit3-oxoacyl-[acyl-carrier-protein] reductaseEstradiol 17-beta-dehydrogenase 8Protein Ke6Short chain dehydrogenase/reductase family 30C member 1Testosterone 17-beta-dehydrogenase 8dJ1033B10.9estrogen 17-oxidoreductasereally interesting new gene 2 proteinFABG

Mechanism of action

NAD-dependent oxidation of 17β-hydroxysteroids to 17-ketosteroids (estradiol to estrone, testosterone to androstenedione) Regulates intratumoral estrogen balance, affecting cell cycle progression in cancer cells (G2/M arrest via estradiol accumulation when inhibited)

Biological functions

Regulation of biologically active estrogens and androgens concentrationsNAD-dependent conversion of estradiol (E2) to estrone (E1)Inactivation of estradiol, testosterone, and dihydrotestosteroneReductive synthesis of estradiol from estroneMitochondrial fatty acid biosynthesisScaffold protein for mitochondrial fatty acid synthase complex assemblyCell proliferation regulation (notably in breast cancer)

Disease associations

Breast cancer (particularly estrogen receptor positive types)Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalitiesMultidrug-resistant tuberculosis (association, not mechanistic)

Safety considerations

Altered activity could affect systemic and intratumoral estrogen/androgen levels, impacting reproductive, metabolic, and oncogenic processes.Possible impact on cell proliferation and cell cycle in hormonally regulated tissues, with implications for cancer biology and potential endocrine side effects

Interacting drugs

No clinically established drugs reported as specific direct interactors in available data; involvement in estrogen metabolism indicates indirect effects by estrogen-based drugs or hormone therapies

Biomarkers

Estrone (E1) and estradiol (E2) levels as markers for HSD17B8 activity and potential role in ER-positive breast cancer prognosis or therapy response

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