ERRβ

ERRβ (ESRRB/NR3B2) is an orphan nuclear receptor transcription factor that shows constitutive transcriptional activity and binds estrogen-related response elements, while no cognate physiological ligand has been identified for ERR family members^[1][2]. Mechanistically, ERRβ supports stem-cell programs: in mouse embryonic stem cells, ESRRB is a pivotal downstream target of the Gsk3/Tcf3 axis that regulates self-renewal^[3]. ERRβ also interacts with Oct4 and positively regulates Nanog expression, linking this receptor to the core pluripotency network^[4]. In trophoblast stem cells, Esrrb acts downstream of Fgf/Mek signaling and directly regulates trophoblast transcription factors, including Elf5 and Eomes, to sustain self-renewal^[5]. In disease models, ERRβ suppresses in vitro and in vivo prostate cancer cell growth through p21^WAF1/CIP1 induction^[6]. Compared with ERRα and ERRγ, which are strongly linked to cellular metabolism and oncogenesis, ERRβ remains distinguished by pluripotency, trophoblast biology, and alternative-splicing-dependent structure and function^[1][2]. For experimental applications, DY131 and phenolic acyl hydrazones selectively activate ERRβ/ERRγ, whereas diethylstilbestrol regulates trophoblast stem-cell differentiation as an ERRβ ligand^[7][8][9].