SphK2, sphingosine kinase 2, phosphorylates sphingosine to sphingosine 1‑phosphate (S1P), a bioactive lipid mediator. SphK2 is involved in multiple biological processes such as histone acetylation regulation, cell proliferation, and inflammation. It participates in pathways like the IL-17 signaling pathway and is associated with diseases including pulmonary hypertension, acute lung injury, heart diseases, obesity, cancer, osteoarthritis, and Alzheimer's disease [1-10].

In disease-related functional studies, SphK2 knockout (KO) mouse models have provided significant insights. In hypoxia-induced pulmonary hypertension, loss of SphK2 inhibited the disease progression and histone H3K9 acetylation [1]. In lipopolysaccharide-induced acute lung injury, knockdown or inhibition of SphK2 decreased oxidative stress, NLRP3 inflammasome activation, and M1 macrophage polarization [2]. In aged SphK2 -/- mice, protection from obesity and insulin resistance was observed, potentially due to enhanced lipolysis and increased adiponectin levels [3]. In colorectal cancer, inhibition of SphK2 reversed 5-fluorouracil resistance [4]. In hepatocellular carcinoma, targeting SphK2 reversed regorafenib resistance [6]. In osteoarthritis, SPHK2 knockdown inhibited the proliferation and migration of fibroblast-like synoviocytes by blocking the IL-17 pathway [5].

In conclusion, SphK2 is a key enzyme in sphingolipid metabolism with diverse functions in various biological processes and diseases. KO mouse models have been instrumental in revealing its role in disease conditions such as pulmonary hypertension, acute lung injury, obesity, insulin resistance, cancer, and osteoarthritis. Understanding SphK2's functions provides potential therapeutic targets for these diseases.

References:

1. Ranasinghe, A Dushani C U, Holohan, Maggie, Borger, Kalyn M, Castellino, Francis J, Schwarz, Margaret A. 2023. Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension. In Circulation research, 133, 704-719. doi:10.1161/CIRCRESAHA.123.322740. https://pubmed.ncbi.nlm.nih.gov/37698017/

2. Gong, Linjing, Shen, Yue, Wang, Sijiao, Hu, Lijuan, Zhu, Lei. 2023. Nuclear SPHK2/S1P induces oxidative stress and NLRP3 inflammasome activation via promoting p53 acetylation in lipopolysaccharide-induced acute lung injury. In Cell death discovery, 9, 12. doi:10.1038/s41420-023-01320-5. https://pubmed.ncbi.nlm.nih.gov/36653338/

3. Ravichandran, Shwetha, Finlin, Brian S, Kern, Philip A, Özcan, Sabire. 2018. Sphk2-/- mice are protected from obesity and insulin resistance. In Biochimica et biophysica acta. Molecular basis of disease, 1865, 570-576. doi:10.1016/j.bbadis.2018.12.012. https://pubmed.ncbi.nlm.nih.gov/30593892/

4. Zhang, Yu-Hang, Shi, Wen-Na, Wu, Shu-Hua, Cui, Shu-Xiang, Qu, Xian-Jun. 2020. SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression. In Oncogene, 39, 5214-5227. doi:10.1038/s41388-020-1352-y. https://pubmed.ncbi.nlm.nih.gov/32546724/

5. Zheng, Jiaxuan, Xiong, Xiaolong, Li, Ke, Cao, Huiyuan, Huang, Hui. 2024. SPHK2 Knockdown Inhibits the Proliferation and Migration of Fibroblast-Like Synoviocytes Through the IL-17 Signaling Pathway in Osteoarthritis. In Journal of inflammation research, 17, 7221-7234. doi:10.2147/JIR.S476077. https://pubmed.ncbi.nlm.nih.gov/39416266/

6. Shi, Weiwei, Zhang, Shan, Ma, Ding, Wu, Junhua, Jiang, Chunping. 2020. Targeting SphK2 Reverses Acquired Resistance of Regorafenib in Hepatocellular Carcinoma. In Frontiers in oncology, 10, 694. doi:10.3389/fonc.2020.00694. https://pubmed.ncbi.nlm.nih.gov/32670862/