SGK1, also known as serum and glucocorticoid-induced kinase-1, belongs to the AGC protein kinase family. It phosphorylates serine and threonine residues of target proteins, regulates numerous ion channels and transporters, and promotes cell survival under stress. SGK1 tightly regulated at transcriptional and post-transcriptional levels is involved in multiple signal transduction pathways related to various biological processes [1,4].

In vascular smooth muscle cells (VSMCs), genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation. In mice, genetic knockout or pharmacological inhibition of Sgk1 by EMD638683 strongly reduced aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation following cholecalciferol overload, and also blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy [2]. In hepatocytes, inhibition of SGK1 by GSK-650394 reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) infiltration, alleviating the recurrence of liver metastasis in the context of hepatic ischemia-reperfusion [3]. In high-fat diet-induced lung fibrosis, the SGK1 specific inhibitor EMD638683 alleviated pulmonary fibrosis and activation of the integrin-inflammasome pathway [5].

In conclusion, SGK1 plays essential roles in multiple biological processes, especially in diseases such as vascular calcification, liver metastasis recurrence, and pulmonary fibrosis. Gene knockout and inhibitor-based studies in mouse models have revealed its functions in these disease conditions, suggesting that targeting SGK1 could be a potential therapeutic strategy for these diseases.

References:

1. Ghani, Madiha Javeed. 2021. SGK1, autophagy and cancer: an overview. In Molecular biology reports, 49, 675-685. doi:10.1007/s11033-021-06836-6. https://pubmed.ncbi.nlm.nih.gov/34669124/

2. Voelkl, Jakob, Luong, Trang Td, Tuffaha, Rashad, Lang, Florian, Alesutan, Ioana. 2018. SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. In The Journal of clinical investigation, 128, 3024-3040. doi:10.1172/JCI96477. https://pubmed.ncbi.nlm.nih.gov/29889103/

3. Li, Xiangdong, Wang, Ziyi, Jiao, Chenyu, Han, Sheng, Pu, Liyong. 2023. Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3. In Journal of translational medicine, 21, 121. doi:10.1186/s12967-023-03977-z. https://pubmed.ncbi.nlm.nih.gov/36788538/

4. Sang, Yiwen, Kong, Piaoping, Zhang, Shizhen, Tao, Zhihua, Liu, Weiwei. 2021. SGK1 in Human Cancer: Emerging Roles and Mechanisms. In Frontiers in oncology, 10, 608722. doi:10.3389/fonc.2020.608722. https://pubmed.ncbi.nlm.nih.gov/33542904/

5. Gu, Xin, Meng, Haoyu, Peng, Chengyi, Jin, Jianliang, Wang, Xiaoyan. . Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. In Clinical and translational medicine, 13, e1308. doi:10.1002/ctm2.1308. https://pubmed.ncbi.nlm.nih.gov/37345264/