HSDL2

HSDL2 Full Name

hydroxysteroid dehydrogenase like 2

HSDL2 Introduction

Hydroxysteroid dehydrogenase-like protein 2 (HSDL2) is a member of the short-chain dehydrogenase/reductase (SDR) superfamily with structural homology to hydroxysteroid dehydrogenases. Encoded by the HSDL2 gene on chromosome 9q32, HSDL2 contains conserved SDR catalytic motifs including a Rossmann-fold NAD(P)H-binding domain and a catalytic triad characteristic of oxidoreductase enzymes. However, its precise endogenous substrate and catalytic function remain incompletely characterized. HSDL2 is localized to the peroxisome, a subcellular organelle involved in fatty acid β-oxidation, reactive oxygen species metabolism, and ether phospholipid biosynthesis.

Figure 1. Strcuture of hydroxysteroid dehydrogenase like 2.

Peroxisomal Localization and Lipid Metabolism
HSDL2 is targeted to peroxisomes by a C-terminal peroxisomal targeting signal type 1 (PTS1) motif (SKL or a related tripeptide) that is recognized by the cytosolic receptor PEX5. Within the peroxisome, HSDL2 is proposed to participate in the metabolism of steroid hormones, bile acid intermediates, or branched-chain fatty acids — substrates commonly processed by peroxisomal SDR enzymes. Recent functional studies have identified HSDL2 as a potential regulator of the peroxisomal fatty acid β-oxidation pathway, with HSDL2 depletion leading to accumulation of very-long-chain fatty acids (VLCFAs), a hallmark of peroxisomal dysfunction. HSDL2 may also contribute to maintaining peroxisomal redox balance through its NAD(P)H-dependent oxidoreductase activity. The protein has additionally been found to interact with PEX19, a peroxin involved in peroxisomal membrane protein import, suggesting a broader role in peroxisome biogenesis.

HSDL2 in Cancer Cell Metabolism and Tumorigenesis
HSDL2 has emerged as a gene of interest in cancer biology, with elevated expression observed in several malignancies. In glioblastoma, HSDL2 is highly expressed and promotes tumor cell proliferation and survival by modulating fatty acid metabolism — its knockdown impairs lipid droplet formation and sensitizes glioma cells to nutrient deprivation-induced apoptosis. In breast cancer, HSDL2 overexpression is associated with poor prognosis, and functional studies indicate that HSDL2 supports cancer cell viability through maintenance of peroxisomal function and detoxification of lipid peroxides. HSDL2 has also been identified as a target of the oncogenic transcription factor c-Myc, providing a mechanistic link between MYC-driven metabolic reprogramming and peroxisomal metabolism in cancer. Pharmacological inhibition or genetic targeting of HSDL2 is being explored as a potential strategy to disrupt the metabolic vulnerabilities of cancer cells.

Alternate Names for HSDL2

HSDL2; hydroxysteroid dehydrogenase like 2; C9orf99, chromosome 9 open reading frame 99; hydroxysteroid dehydrogenase-like protein 2; SDR13C1; short chain dehydrogenase/reductase family 13C; member 1; short chain dehydrogenase/reductase family 13C, member 1; C9orf99; FLJ25855; MGC10940;