Eda2r, short for ectodysplasin A2 receptor, is a member of the tumor necrosis factor receptor (TNFR) superfamily [3]. It plays a crucial role in multiple biological processes. Its ligand is EDA-A2, and it is involved in the non-canonical NFκB pathway with NFκB-inducing kinase (NIK) as a downstream mediator [1,2,5]. Eda2r is important in normal prenatal development and has implications in various pathophysiological conditions [4]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In cancer cachexia, gene expression analysis showed upregulation of Eda2r in muscle tissues of tumour-bearing mice and cachectic cancer patients [1]. Activation of Eda2r by EDA-A2 promoted atrophy in cultured myotubes and muscle tissue, which was NIK-dependent [1,2]. Mice lacking Eda2r or NIK were protected from tumour-induced muscle loss [1,2]. In the context of other diseases, in high-glucose-induced podocyte injury, Eda2r expression increased in kidney cells, and its overexpression promoted podocyte apoptosis [3]. In hyperoxia-induced lung epithelial cell injury, knockdown of Eda2r alleviated cell injury by inhibiting the NF-κB pathway [4]. In myocardial ischemia/reperfusion injury, Eda2r knockdown exerted anti-apoptotic and antioxidant effects by suppressing the NF-κB signaling pathway [6].

In conclusion, Eda2r is involved in multiple pathophysiological processes. Through studies using KO mouse models, it has been revealed that Eda2r plays a significant role in cancer-associated muscle atrophy, podocyte injury, hyperoxia-induced lung epithelial cell injury, and myocardial ischemia/reperfusion injury. These findings provide potential therapeutic targets for related diseases.

References:

1. Bilgic, Sevval Nur, Domaniku, Aylin, Toledo, Batu, Loumaye, Audrey, Kir, Serkan. 2023. EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia. In Nature, 617, 827-834. doi:10.1038/s41586-023-06047-y. https://pubmed.ncbi.nlm.nih.gov/37165186/

2. Agca, Samet, Kir, Serkan. 2024. EDA2R-NIK signaling in cancer cachexia. In Current opinion in supportive and palliative care, 18, 126-131. doi:10.1097/SPC.0000000000000705. https://pubmed.ncbi.nlm.nih.gov/38801457/

3. Lan, Xiqian, Kumar, Vinod, Jha, Alok, Malhotra, Ashwani, Singhal, Pravin C. 2020. EDA2R mediates podocyte injury in high glucose milieu. In Biochimie, 174, 74-83. doi:10.1016/j.biochi.2020.04.003. https://pubmed.ncbi.nlm.nih.gov/32304771/

4. Jia, Nan, Jia, Yi, Yang, Fen, Du, Wenchao. 2022. Knockdown of EDA2R alleviates hyperoxia-induced lung epithelial cell injury by inhibiting NF-κB pathway. In Allergologia et immunopathologia, 50, 84-90. doi:10.15586/aei.v50i5.670. https://pubmed.ncbi.nlm.nih.gov/36086968/

5. Özen, Sevgi Döndü, Kir, Serkan. 2024. Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology. In Trends in molecular medicine, 30, 471-483. doi:10.1016/j.molmed.2024.02.002. https://pubmed.ncbi.nlm.nih.gov/38443222/

6. Guan, Zhi-Hui, Yang, Di, Wang, Yi, Ma, Jia-Bin, Wang, Guo-Nian. 2024. Ectodysplasin-A2 receptor (EDA2R) knockdown alleviates myocardial ischemia/reperfusion injury through inhibiting the activation of the NF-κB signaling pathway. In Experimental animals, 73, 376-389. doi:10.1538/expanim.24-0020. https://pubmed.ncbi.nlm.nih.gov/38797667/