Entr1, also known as SDCCAG3, is an endosome-associated trafficking regulator. It is crucial for protein trafficking and has been implicated in various biological processes [1,2,3,5]. Entr1 may be involved in pathways related to cell surface receptor regulation, adipogenesis, and macrophage polarization, which are important for normal physiological functions and disease-related processes [1,2,4]. Genetic models, especially KO/CKO mouse models, can be valuable in further elucidating its functions.

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 was found to directly interact with AMP-activated protein kinase (AMPK), enhancing its phosphorylation, and the inhibitory effect of Entr1 on macrophage M1 polarization was attenuated by the AMPK inhibitor Compound C. This indicates that Entr1 regulates periodontitis by suppressing macrophage M1 polarization through enhancing AMPK phosphorylation [1]. In hyperlipidemia-induced osteoporosis studies, 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. AN698/40746067, which targets Entr1 to suppress PPARγ, attenuated adipogenesis in vivo [2].

In conclusion, Entr1 plays essential roles in processes like macrophage polarization and adipogenesis. The KO/CKO mouse model-based research has revealed its significance in periodontitis and hyperlipidemia-induced osteoporosis, suggesting Entr1 as a potential therapeutic target for these diseases.