Esrra, also known as estrogen-related receptor alpha, is an orphan nuclear receptor that acts as a transcription factor. It plays a crucial role in multiple biological processes such as mitochondrial biogenesis, autophagy, and metabolic stress response. It is associated with pathways like E2/ESR1 signaling, and is important for maintaining cellular homeostasis and energy metabolism [1,2,5]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions.

In adipocyte-rich bone marrow, adipocyte-specific Esrra deficiency promotes osteogenesis and vascular formation, interfering with E2/ESR1 signaling and modulating leptin and Spp1 expression [1]. In the intestine, Esrra-deficient mice show increased susceptibility to DSS-induced colitis, with disrupted autophagic flux, abnormal gut microbiota, and decreased AMP-activated protein kinase phosphorylation [2]. In the kidney, Esrra couples metabolism and differentiation in proximal tubule cells, protecting from kidney disease [3]. In metabolic dysfunction-associated steatohepatitis, Esrra regulates Rplp1-mediated translation of lysosome proteins, and this is reversed by alternate day fasting [4].

In conclusion, Esrra is essential for maintaining normal physiological functions in various tissues. KO and CKO mouse models have revealed its role in diseases such as bone loss, colitis, kidney disease, and metabolic-associated liver diseases. Understanding Esrra's functions provides potential therapeutic targets for these disease areas.