DHRS9, also known as SDR9C4, is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. It is involved in multiple biological functions such as the metabolism of bioactive oxylipins, which play roles in inflammation and the immune response [7]. It can oxidize oxylipins with hydroxyl groups at specific carbon positions of octadecanoids, eicosanoids, and docosanoids. It is also related to the synthesis of allopregnanolone from progesterone, which controls neuronal excitability [5]. In addition, it is a retinol-metabolizing enzyme, mediating the conversion of retinol into retinoic acid [6].

In various diseases, DHRS9 shows different expression patterns and effects. In pancreatic cancer, it is overexpressed, and high expression is correlated with poor prognosis and may affect the oncological process through the MAPK/ERK pathway [1]. In atherosclerosis, it is upregulated in macrophages of atherosclerotic lesions and could be a novel potential target, with its pro-atherogenic effect mediated by the immune mechanism [2]. In contrast, in colorectal cancer and oral squamous cell carcinoma, DHRS9 is downregulated, and low expression is associated with tumor progression and poor prognosis [3,4]. Mice deficient in DHRS9 protein have lower oxidative activity of microsomal membranes from certain tissues towards specific oxylipins, suggesting its role in oxylipin metabolism in vivo [7].

In summary, DHRS9 has diverse functions in lipid mediator metabolism, retinol-retinoic acid conversion, and is associated with neuronal excitability regulation. Its abnormal expression is linked to multiple diseases, and gene-knockout mouse models have helped to reveal its role in oxylipin metabolism. Understanding DHRS9 is crucial for uncovering disease mechanisms and may provide potential targets for treatment in cancer, atherosclerosis, and potentially epilepsy-related conditions.

References:

1. Li, Huang-Bao, Zhou, Jun, Zhao, Fengqing, Yu, Jiayin, Xu, Longsheng. 2020. Prognostic Impact of DHRS9 Overexpression in Pancreatic Cancer. In Cancer management and research, 12, 5997-6006. doi:10.2147/CMAR.S251897. https://pubmed.ncbi.nlm.nih.gov/32765099/

2. Xu, Jinling, Zhou, Hui, Cheng, Yangyang, Xiang, Guangda. 2022. Identifying potential signatures for atherosclerosis in the context of predictive, preventive, and personalized medicine using integrative bioinformatics approaches and machine-learning strategies. In The EPMA journal, 13, 433-449. doi:10.1007/s13167-022-00289-y. https://pubmed.ncbi.nlm.nih.gov/36061826/

3. Hu, Liang, Chen, Hai-Yang, Han, Tao, Cai, Qing-Ping, Gao, Chun-Fang. 2015. Downregulation of DHRS9 expression in colorectal cancer tissues and its prognostic significance. In Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 37, 837-45. doi:10.1007/s13277-015-3880-6. https://pubmed.ncbi.nlm.nih.gov/26254099/

4. Shimomura, Hiroyuki, Sasahira, Tomonori, Nakashima, Chie, Shimomura-Kurihara, Miyako, Kirita, Tadaaki. 2018. Downregulation of DHRS9 is associated with poor prognosis in oral squamous cell carcinoma. In Pathology, 50, 642-647. doi:10.1016/j.pathol.2018.06.002. https://pubmed.ncbi.nlm.nih.gov/30149992/

5. Calì, Francesco, Elia, Maurizio, Vinci, Mirella, Vanadia, Francesca, Romano, Valentino. 2020. Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report. In Medicina (Kaunas, Lithuania), 56, . doi:10.3390/medicina56080387. https://pubmed.ncbi.nlm.nih.gov/32752300/

6. Jones, Richard J, Dickerson, Sarah, Bhende, Prassana M, Delecluse, Henri-Jacque, Kenney, Shannon C. 2007. Epstein-Barr virus lytic infection induces retinoic acid-responsive genes through induction of a retinol-metabolizing enzyme, DHRS9. In The Journal of biological chemistry, 282, 8317-24. doi:. https://pubmed.ncbi.nlm.nih.gov/17244623/

7. Belyaeva, Olga V, Wirth, Samuel E, Boeglin, William E, Brash, Alan R, Kedishvili, Natalia Y. 2021. Dehydrogenase reductase 9 (SDR9C4) and related homologs recognize a broad spectrum of lipid mediator oxylipins as substrates. In The Journal of biological chemistry, 298, 101527. doi:10.1016/j.jbc.2021.101527. https://pubmed.ncbi.nlm.nih.gov/34953854/