ENTR1, also known as SDCCAG3, is an endosome-associated trafficking regulator. It is crucial for protein trafficking and has been implicated in various cellular processes. It may be involved in pathways related to cell-surface receptor regulation, as it controls the delivery of Fas from endosomes to lysosomes [3]. It also potentially has a role in the transcriptional regulation of the solute carrier family 2 member 1 glucose transporter protein (SLC2A1) [4].

In a ligature-induced periodontitis mouse model, ENTR1 expression was down-regulated in periodontitis mice. Overexpressing ENTR1 suppressed macrophage M1 polarization and mitigated bone loss, while knocking down ENTR1 exacerbated these effects. ENTR1 directly interacted with AMP-activated protein kinase (AMPK), enhancing its phosphorylation, and the inhibitory impact of ENTR1 on macrophage M1 polarization and inflammation-induced alveolar bone resorption were partially attenuated by the AMPK inhibitor Compound C [1]. In hyperlipidemia-induced osteoporosis, ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain-and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression [2].

In conclusion, ENTR1 is involved in important cellular processes. Through gene knockout or loss-of-function models, it has been shown to play a role in periodontitis by regulating macrophage polarization via AMPK activation and in hyperlipidemia-induced osteoporosis by facilitating adipogenesis. These findings highlight its potential as a therapeutic target in these disease areas.

References:

1. Wang, Xi, Gui, Houda, Liu, Chenghang, Ma, Anquan, Lan, Jing. 2025. ENTR1 regulates periodontitis by modulating macrophage M1 polarization via AMPK activation. In Life sciences, 369, 123525. doi:10.1016/j.lfs.2025.123525. https://pubmed.ncbi.nlm.nih.gov/40054733/

2. Ren, Huiping, Mao, Kai, Yuan, Xin, Ye, Zhou, Lan, Jing. 2024. AN698/40746067 suppresses bone marrow adiposity to ameliorate hyperlipidemia-induced osteoporosis through targeted inhibition of ENTR1. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 176, 116843. doi:10.1016/j.biopha.2024.116843. https://pubmed.ncbi.nlm.nih.gov/38810405/

3. Sharma, Shruti, Carmona, Antonio, Skowronek, Agnieszka, Tseng, Pei-Li, Erdmann, Kai S. 2019. Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95. In Nature communications, 10, 3105. doi:10.1038/s41467-019-11025-y. https://pubmed.ncbi.nlm.nih.gov/31308371/

4. Farries, Gabriella, Bryan, Kenneth, McGivney, Charlotte L, Katz, Lisa Michelle, Hill, Emmeline W. 2019. Expression Quantitative Trait Loci in Equine Skeletal Muscle Reveals Heritable Variation in Metabolism and the Training Responsive Transcriptome. In Frontiers in genetics, 10, 1215. doi:10.3389/fgene.2019.01215. https://pubmed.ncbi.nlm.nih.gov/31850069/