Egln3, also known as egl-9 family hypoxia-inducible factor 3, is a hypoxia response factor. It belongs to the Egln family of proline hydroxylases and is involved in regulating various biological processes. It can regulate transcription, the cell cycle, and apoptosis through hydroxylation, ubiquitylation, and participation in glycolysis. It is also associated with multiple signaling pathways such as PI3K/AKT, MAPK, and NF-κB pathways, playing a significant role in maintaining endothelial function, vascular homeostasis, and influencing cell proliferation, angiogenesis, and immune responses [1,2,5,6,7]. Genetic models like knockout (KO) or conditional knockout (CKO) mice are valuable for studying Egln3's functions.

In gastric cancer, restoration of Egln3 expression inhibited cell proliferation and metastasis by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway independent of its hydroxylase activity [1]. In subarachnoid hemorrhage, endothelial Egln3-PKM2 signaling induced the formation of an acute astrocytic barrier to alleviate immune cell infiltration [2]. In lung adenocarcinoma, Egln3 was overexpressed, correlated with poor prognosis, and regulated DDR-related pathways and TGF-β signaling, leading to resistance to chemotherapy and immunotherapy [3]. In hepatic encephalopathy, knockdown of Egln3 protected neurons from ammonia-induced apoptosis through the mitochondrial-dependent apoptosis pathway [4]. In pulmonary hypertension, endothelial cell-specific knockout of Egln3 decelerated the disease progression, while overexpression had the opposite effect, with Egln3 under hypoxia interacting with HUR to enhance EGFR mRNA stability and activate PI3K/AKT and MAPK signaling pathways [5]. In lung cancer, inactivation of Egln3 hydroxylase facilitated Erk3 degradation via autophagy, reprogrammed the tumor microenvironment, and impeded cancer growth [6]. In Alzheimer's disease, inhibition of Egln3 expression in APP/PS1 mice improved neuroinflammatory responses and cognitive function as Egln3 could activate the MAPK pathway to exacerbate neuroinflammation [7]. In androgenetic alopecia, reduction of Egln3 stimulated proliferation of dermal papilla cells and promoted hair follicle growth in ex vivo studies [8]. In renal cell carcinoma, silencing of circular RNA Egln3 repressed tumor progression through the miR-1224-3p/HMGXB3 axis [9].

In conclusion, Egln3 is crucial in multiple biological processes and diseases. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its diverse roles in cancer, neurodegenerative diseases, cardiovascular diseases, and other conditions. These findings contribute to understanding the underlying mechanisms of these diseases and suggest Egln3 as a potential therapeutic target.