School of Chemistry & Chemical Engineering, Qilu University of Technology, Shandong Academy of Sciences, 3501 Da Xue Road, Jinan, 250353, China.
Department of Pharmacy, Huashan Hospital, Fudan University, 108 Luxiang Road, Shanghai 201907, China.
Curr Med Chem. 2024;31(24):3653-3667. doi: 10.2174/0929867330666230518140631.
Estrogen-related receptor gamma (ERRγ), one of three members of the ERR family, is an inducible transcription factor. ERRγ has dual functions in different tissues. The decreased expression of ERRγ in the brain, stomach, prostate, and fat cells can cause neuropsychological dysfunction, gastric cancer, prostate cancer, and obesity. However, when ERRγ is present in the liver, pancreas, and thyroid follicular cells, ERRγ overexpression is related to liver cancer, type II diabetes, oxidative liver injury, and anaplastic thyroid carcinoma. Signaling pathway studies have confirmed that ERRγ agonists or inverse agonists can regulate ERRγ expression to treat related diseases. The collision between residue Phe435 and the modulator is a key factor determining the activation or inhibition of ERRγ. Although more than 20 agonists and inverse agonists of ERRγ have been reported, no clinical studies have been found in the literature. This review summarizes the important relationship between ERRγ-related signaling pathways and diseases, research progress, and the structure-activity relationship of modulators. These findings provide guidance for further study on new ERRγ modulators.
雌激素相关受体γ（ERRγ）是 ERR 家族的三个成员之一，是一种可诱导的转录因子。ERRγ 在不同组织中具有双重功能。ERRγ 在大脑、胃、前列腺和脂肪细胞中的表达减少会导致神经心理功能障碍、胃癌、前列腺癌和肥胖。然而，当 ERRγ 存在于肝脏、胰腺和甲状腺滤泡细胞中时，ERRγ 的过表达与肝癌、II 型糖尿病、氧化肝损伤和间变性甲状腺癌有关。信号通路研究证实，ERRγ 激动剂或反向激动剂可以调节 ERRγ 的表达来治疗相关疾病。残基 Phe435 与调节剂的碰撞是决定 ERRγ 激活或抑制的关键因素。尽管已经报道了超过 20 种 ERRγ 的激动剂和反向激动剂，但文献中尚未发现临床研究。本综述总结了 ERRγ 相关信号通路与疾病的重要关系、研究进展以及调节剂的构效关系。这些发现为进一步研究新型 ERRγ 调节剂提供了指导。
