ERRγ

ERRγ (ESRRG/NR3B3) is a constitutively active nuclear receptor that functions as a transcriptional regulator without an identified physiological ligand^[1]. Mechanistically, ERRγ coordinates oxidative metabolism: in skeletal muscle, ERRγ expression drives fat metabolism, mitochondrial respiration, type I fiber specification, angiogenesis, mitochondrial biogenesis, antioxidant defense, and oxidative remodeling^[2][3]. In cardiac muscle, ERRα and ERRγ jointly regulate cardiomyocyte metabolism and function, showing functional overlap in high-energy tissues^[4]. In liver models, ERRγ coordinates endocrine and metabolic signals that alter glucose, lipid, alcohol, and iron metabolism, linking ERRγ dysregulation to hyperglycemia, insulin resistance, and alcoholic liver injury^[5]. In cancer models, ERRγ induces E-cadherin, promotes mesenchymal-to-epithelial transition, and suppresses breast tumor growth, while gastric cancer studies identify ESRRG as a negative regulator of Wnt signaling and a tumor suppressor^[6][7]. Compared with related isoforms, ERRα and ERRγ share metabolic transcriptional roles, whereas ERRβ is less defined metabolically and is linked more strongly to embryonic stem cell pluripotency^[8]. For experimental applications, GSK5182 suppresses ERRγ-driven hepatic gluconeogenesis, while DY131 activates ESRRG-dependent suppression of gastric cancer growth and Wnt signaling^[5][7].