HK3, short for Hexokinase 3, is a key enzyme in glucose phosphorylation, the initial step of most glucose metabolic pathways. This process is fundamental for energy production and various cellular functions. The gene is involved in energy metabolism-a crucial aspect of cell survival and proliferation [1,3,4,6,7].

In glioma, HK3 significantly stimulates immune cell infiltration into the tumor microenvironment (TME), with higher HK3 expression correlating with increased infiltration of M2 macrophages, neutrophils, and activated memory CD4+ T cells. HK3 expression also rises with tumor grade, is higher in the mesenchymal subtype of glioblastoma (GBM), and independently predicts poor outcomes in GBM patients [1]. In clear cell renal cell carcinoma (ccRCC), HK3 is a key regulator of O-GlcNAcylation of EP300, which promotes PD-L1 transcription and protein stability, aiding tumor immune evasion [2]. In renal cell carcinoma (RCC), circZBTB44 promotes RCC progression by up-regulating HK3, which exerts oncogenic effects on RCC cell behaviors and tumor growth, and also promotes M2 polarization of macrophages [3]. In neuroblastoma (NB), HK3 not only directly regulates tumor cell malignant behaviors but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis [4]. In hepatocellular carcinoma (HCC), HK3 is a novel prognostic biomarker, and its up-regulation reduces HCC cell metastasis [5]. In glioblastoma multiforme (GBM), HK3 expression is upregulated, correlates with poor prognosis, and is associated with immune response and drug resistance [6]. In non-small cell lung cancer (NSCLC), HK3 expression is related to immune status and predicts the efficacy of immunotherapy [7]. In sepsis-induced acute lung injury, HK3 is a hub gene with diagnostic and prognostic significance, and its knockdown affects cell proliferation, glycolytic flux, inflammatory response, oxidative stress, and apoptosis [8].

In summary, HK3 plays a crucial role in multiple disease conditions, mainly through its involvement in energy metabolism and immune-related processes. Research on HK3, especially using in vivo models like gene knockout or conditional knockout mouse models, has provided insights into its functions in various cancers and sepsis-induced acute lung injury, potentially offering new therapeutic targets for these diseases.

References:

1. Li, Shupeng, Li, Ziwei, Wang, Xinyu, Meng, Xiangqi, Cai, Jinquan. 2023. HK3 stimulates immune cell infiltration to promote glioma deterioration. In Cancer cell international, 23, 227. doi:10.1186/s12935-023-03039-w. https://pubmed.ncbi.nlm.nih.gov/37779195/

2. Zhang, Wei, Zhao, Enyang, Li, Zhuolun, Li, Xuedong, You, Bosen. 2024. Hexokinase HK3-mediated O-GlcNAcylation of EP300: a key regulator of PD-L1 expression and immune evasion in ccRCC. In Cell death & disease, 15, 613. doi:10.1038/s41419-024-06921-1. https://pubmed.ncbi.nlm.nih.gov/39179546/

3. Li, Tushuai, Gu, Yue, Xu, Baocai, Zhang, Jie, Wu, Wenda. 2023. CircZBTB44 promotes renal carcinoma progression by stabilizing HK3 mRNA structure. In Molecular cancer, 22, 77. doi:10.1186/s12943-023-01771-5. https://pubmed.ncbi.nlm.nih.gov/37106446/

4. Wu, Xin, Mi, Tao, Jin, Liming, Guo, Peng, He, Dawei. 2024. Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma. In Cancer immunology, immunotherapy : CII, 73, 122. doi:10.1007/s00262-024-03702-9. https://pubmed.ncbi.nlm.nih.gov/38714539/

5. Du, Yexiang, Zhang, Hongchuan, Liu, Jialong, Chen, Suhua, Jiang, Wenbin. 2024. HK3: A potential prognostic biomarker with metastasis inhibition capabilities in hepatocellular carcinoma. In Biochemical and biophysical research communications, 741, 151057. doi:10.1016/j.bbrc.2024.151057. https://pubmed.ncbi.nlm.nih.gov/39615209/

6. Yang, Yuling, Fu, Xing, Liu, Runsha, Yan, Lijuan, Yang, Yiping. 2023. Exploring the prognostic value of HK3 and its association with immune infiltration in glioblastoma multiforme. In Frontiers in genetics, 13, 1033572. doi:10.3389/fgene.2022.1033572. https://pubmed.ncbi.nlm.nih.gov/36712881/

7. Tuo, Zhan, Zheng, Xin, Zong, Yan, Lv, Yi, Liu, Jun. . HK3 is correlated with immune infiltrates and predicts response to immunotherapy in non-small cell lung cancer. In Clinical and translational medicine, 10, 319-330. doi:10.1002/ctm2.6. https://pubmed.ncbi.nlm.nih.gov/32508023/

8. Zhu, Mingyu, Tang, Xiaokai, Xu, Jingjing, Gong, Yuanqi. 2024. Identification of HK3 as a promising immunomodulatory and prognostic target in sepsis-induced acute lung injury. In Biochemical and biophysical research communications, 706, 149759. doi:10.1016/j.bbrc.2024.149759. https://pubmed.ncbi.nlm.nih.gov/38484574/