Esr2, also known as estrogen receptor β, is a nuclear estrogen receptor. It contributes to the actions of estrogen in various physiological phenomena, and is involved in multiple pathways [3,6]. Estrogens, along with their receptors including Esr2, regulate male reproductive and non-reproductive organs, and also play a role in female-related physiological processes like glycemic homeostasis [3,4].

In terms of disease associations, studies on Esr2 gene polymorphisms show that the rs1256049 polymorphism in the ESR2 gene is associated with a higher risk of prostate cancer in the Caucasian population and a lower risk in the Asian population [1]. In knee osteoarthritis, Lipoxin A4 can inhibit fibroblast-like synoviocytes ferroptosis by activating the Esr2/LPAR3/Nrf2 axis, alleviating pain and pathological progression [2]. Regarding glycemic homeostasis, Esr2-mediated effects are considered detrimental, with an imbalance of the ESR1/ESR2 ratio having potential metabolic consequences [4]. In breast cancer, the rs1256030 variant of the ESR2 gene and haplotype GAT were associated with susceptibility as risk factors in the Mexican population [5].

In conclusion, Esr2 is crucial for estrogen-mediated physiological functions. Research on Esr2, especially through gene-related studies such as those on its polymorphisms, has revealed its associations with diseases like prostate cancer, knee osteoarthritis, glycemic-related disorders, and breast cancer. Understanding Esr2's role provides insights into the mechanisms of these diseases and may offer potential targets for treatment.

References:

1. Chang, Xueliang, Wang, Hu, Yang, Zhan, Li, Jingdong, Han, Zhenwei. . ESR2 polymorphisms on prostate cancer risk: A systematic review and meta-analysis. In Medicine, 102, e33937. doi:10.1097/MD.0000000000033937. https://pubmed.ncbi.nlm.nih.gov/37335680/

2. Hu, Zhehan, Chen, Liang, Zhao, Jihui, Shen, Peng, Yang, Yue. 2024. Lipoxin A4 ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes. In Redox biology, 73, 103143. doi:10.1016/j.redox.2024.103143. https://pubmed.ncbi.nlm.nih.gov/38754271/

3. Cooke, Paul S, Nanjappa, Manjunatha K, Ko, CheMyong, Prins, Gail S, Hess, Rex A. . Estrogens in Male Physiology. In Physiological reviews, 97, 995-1043. doi:10.1152/physrev.00018.2016. https://pubmed.ncbi.nlm.nih.gov/28539434/

4. Gregorio, Karen Cristina Rego, Laurindo, Caroline Pancera, Machado, Ubiratan Fabres. 2021. Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. In Cells, 10, . doi:10.3390/cells10010099. https://pubmed.ncbi.nlm.nih.gov/33430527/

5. Gallegos-Arreola, Martha Patricia, Zúñiga-González, Guillermo M, Figuera, Luis E, Gómez-Meda, Belinda Claudia, Rosales-Reynoso, Mónica Alejandra. 2022. ESR2 gene variants (rs1256049, rs4986938, and rs1256030) and their association with breast cancer risk. In PeerJ, 10, e13379. doi:10.7717/peerj.13379. https://pubmed.ncbi.nlm.nih.gov/35573183/

6. Morishita, Masahiro, Higo, Shimpei, Iwata, Kinuyo, Ishii, Hirotaka. 2023. Sex and interspecies differences in ESR2-expressing cell distributions in mouse and rat brains. In Biology of sex differences, 14, 89. doi:10.1186/s13293-023-00574-z. https://pubmed.ncbi.nlm.nih.gov/38111056/