Egln3, also known as egl-9 family hypoxia-inducible factor 3, is a hypoxia response factor involved in multiple biological processes. It is a member of the Egln family of proline hydroxylases, regulating processes such as transcription, the cell cycle, and apoptosis through hydroxylation, ubiquitylation, and participation in glycolysis. It also interacts with key signaling pathways like NF-κB, MAPK, PI3K/AKT, and is associated with various physiological and pathological conditions [1,5,7].

In cancer, Egln3 shows diverse roles. In gastric cancer, its expression is reduced, and restoring it inhibits cell proliferation and metastasis by downregulating JMJD8-mediated activation of the NF-κB pathway independent of hydroxylase activity [1]. In lung adenocarcinoma, it is overexpressed, predicting resistance to immunotherapy and chemotherapy, as it regulates DDR-related pathways and TGF-β signaling [2]. In lung cancer, inactivation of its hydroxylase facilitates Erk3 degradation via autophagy, impeding cancer growth by reprogramming the tumor microenvironment [4]. In renal cell carcinoma, circular RNA derived from EGLN3 promotes tumor progression through the miR-1224-3p/HMGXB3 axis [9]. In hepatic encephalopathy, knockdown of Egln3 protects neurons from ammonia-induced apoptosis through the mitochondrial-dependent apoptosis pathway [3]. In Alzheimer's disease, its high expression in microglia exacerbates neuroinflammation and promotes disease progression via the MAPK pathway [5]. In subarachnoid hemorrhage, endothelial EGLN3-PKM2 signaling induces the formation of an acute astrocytic barrier to alleviate immune cell infiltration [6]. In pulmonary hypertension, Egln3 is upregulated in the remodeled pulmonary artery endothelium, and its endothelial-cell-specific knockout decelerates disease progression [7]. In androgenetic alopecia, reduction of EGLN3 stimulates dermal papilla cell proliferation and promotes hair follicle growth [8].

In conclusion, Egln3 plays crucial roles in multiple diseases including various cancers, neurodegenerative diseases, and other pathological conditions. Studies using gene-knockout or conditional-knockout mouse models, along with in vitro and in vivo experiments, have revealed its diverse functions in regulating cell proliferation, apoptosis, inflammation, and signaling pathways, providing potential therapeutic targets for these diseases.

References:

1. Cai, Fenglin, Yang, Xiuding, Ma, Gang, Dong, Cheng, Deng, Jingyu. 2024. EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity. In British journal of cancer, 130, 597-612. doi:10.1038/s41416-023-02546-x. https://pubmed.ncbi.nlm.nih.gov/38184692/

2. Sun, Shijie, Wang, Kai, Guo, Deyu, Shen, Hongchang, Du, Jiajun. 2024. Identification of the key DNA damage response genes for predicting immunotherapy and chemotherapy efficacy in lung adenocarcinoma based on bulk, single-cell RNA sequencing, and spatial transcriptomics. In Computers in biology and medicine, 171, 108078. doi:10.1016/j.compbiomed.2024.108078. https://pubmed.ncbi.nlm.nih.gov/38340438/

3. Li, Jiequn, Chen, Chunli, Li, Chenchen, Tan, Jieqiong, Zeng, Liuwang. 2022. Genome-Wide Knockout Screen Identifies EGLN3 Involving in Ammonia Neurotoxicity. In Frontiers in cell and developmental biology, 10, 820692. doi:10.3389/fcell.2022.820692. https://pubmed.ncbi.nlm.nih.gov/35425766/

4. Jin, Ying, Pan, Yamu, Zheng, Shuang, Yuan, Ye, Fu, Jian. 2022. Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth. In Oncogene, 41, 1752-1766. doi:10.1038/s41388-022-02203-2. https://pubmed.ncbi.nlm.nih.gov/35124697/

5. Guan, Jiaxin, Wu, Pengfei, Liu, Meiling, Fan, Ying, Gan, Lu. 2024. Egln3 expression in microglia enhances the neuroinflammatory responses in Alzheimer's disease. In Brain, behavior, and immunity, 125, 21-32. doi:10.1016/j.bbi.2024.12.022. https://pubmed.ncbi.nlm.nih.gov/39701332/

6. Duan, Mingxu, Ru, Xufang, Zhou, Jiru, Feng, Hua, Chen, Yujie. 2024. Endothelial EGLN3-PKM2 signaling induces the formation of acute astrocytic barrier to alleviate immune cell infiltration after subarachnoid hemorrhage. In Fluids and barriers of the CNS, 21, 42. doi:10.1186/s12987-024-00550-8. https://pubmed.ncbi.nlm.nih.gov/38755642/

7. Deng, Xiaodong, Que, Qing, Zhang, Kunchi, Lv, Sheng, Liu, Yi. 2025. Mechanistic insights into the role of EGLN3 in pulmonary vascular remodeling and endothelial dysfunction. In Respiratory research, 26, 61. doi:10.1186/s12931-025-03144-6. https://pubmed.ncbi.nlm.nih.gov/39985019/

8. Liu, Qingmei, Tang, Yulong, Huang, Yan, Lin, Jinran, Wu, Wenyu. 2022. Insights into male androgenetic alopecia using comparative transcriptome profiling: hypoxia-inducible factor-1 and Wnt/β-catenin signalling pathways. In The British journal of dermatology, 187, 936-947. doi:10.1111/bjd.21783. https://pubmed.ncbi.nlm.nih.gov/35862273/

9. Zhang, Gang, Wang, Jianqiang, Tan, Wei, Sun, Yi, Li, Hang. 2021. Circular RNA EGLN3 silencing represses renal cell carcinoma progression through the miR-1224-3p/HMGXB3 axis. In Acta histochemica, 123, 151752. doi:10.1016/j.acthis.2021.151752. https://pubmed.ncbi.nlm.nih.gov/34274607/