H6pd, also known as hexose-6-phosphate dehydrogenase, is a microsomal enzyme that catalyzes the first two reactions of the oxidative chain of the pentose phosphate pathway [3]. This pathway is crucial for generating NADPH, which is involved in various cellular processes such as antioxidant defense, lipid biosynthesis, and steroid hormone metabolism. H6pd is located in the lumen of the endoplasmic reticulum and is particularly important in the context of corticosteroid metabolism, as it provides the NADPH required for the oxo-reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (11-HSD1) [2].

Mice carrying a targeted mutation in H6pd have drastically decreased 11-HSD1 oxo-reductase activity, but increased 11-dehydrogenase activity [2]. These mice exhibit many phenotypic features similar to those with a mutation of 11-HSD1 itself, highlighting the significance of H6pd in corticosteroid metabolism. In addition, in cultured human amnion fibroblasts, small interfering RNA-mediated knockdown of H6PD expression significantly attenuated the conversion of cortisone to cortisol, further demonstrating its role in this metabolic process [5].

In terms of disease associations, in a case-control study of Iranian Kurdish women, variants of H6PD R453Q were found to affect the risk of polycystic ovary syndrome (PCOS), with statistically significant lower frequencies of certain genotypes and alleles in PCOS patients compared to controls [3]. Also, in gallbladder cancer, miR-551b-3p was shown to target and inhibit H6PD expression, and overexpression of miR-551b-3p suppressed epithelial-mesenchymal transition, migration, and invasion of cancer cells by inhibiting H6PD [1]. In retinoblastoma, long noncoding RNA TUG1 promoted cancer progression by sponging miR-516b-5p to upregulate H6PD expression [4].

In conclusion, H6pd plays an essential role in the pentose phosphate pathway, especially in providing NADPH for corticosteroid metabolism. The study of H6pd knockout mouse models has revealed its significance in this metabolic process. Additionally, research on H6pd has shown its potential associations with diseases such as PCOS, gallbladder cancer, and retinoblastoma, contributing to a better understanding of the disease mechanisms and potentially paving the way for new therapeutic strategies.