Esrra, also known as estrogen-related receptor alpha, is an orphan nuclear receptor. It acts as a transcription factor and is a key regulator in multiple biological processes, being highly expressed in organs with exuberant metabolism. It is involved in mitochondrial biogenesis, macroautophagy/autophagy function, and responds to metabolic stress [1,2,3,4,5,6,7,8,9,10].

In adipocyte-rich bone marrow, adipocyte-specific Esrra deficiency promotes osteogenesis and vascular formation. Mechanistically, Esrra in adipocytes interferes with E2/ESR1 signaling, represses Spp1 transcription, and positively modulates leptin expression. Abrogation of Esrra leads to enhanced SPP1 and decreased leptin secretion, influencing bone marrow stromal stem cell fate and restoring type H vessel formation [1].

In the intestine, Esrra-deficient mice are more susceptible to DSS-induced colitis, with depressed AMP-activated protein kinase phosphorylation, lower TFEB levels, and defective mitochondria. The gut microbiota composition in these mice is distinct, and fecal microbiota transplantation from wild-type mice can ameliorate colitis severity [2].

In the kidney, single-cell RNA sequencing identified Esrra as a key factor coupling 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, which is downregulated during the disease but can be reversed by alternate day fasting [4].

In gastric cancer, ESRRA promotes cancer development through the DSN1-regulated CDC25C/CDK1/CyclinB1 pathway [5].

In diabetic tubular injury, the decline of Esrra expression is implicated in reduced mitochondrial mass, and empagliflozin can mitigate this by modulating Esrra [6].

In endometrial cancer, ESRRA is highly expressed, associated with poor prognosis, and knockdown of ESRRA inhibits cell proliferation [7].

During prolonged starvation, ESRRA acts as a master regulator of adaptive hepatic translation by stimulating Rplp1 gene expression [8].

In innate host defense, ESRRA is required for autophagy activation against mycobacterial infection, enhancing transcriptional activation of autophagy-related genes and operating in a feed-forward loop with SIRT1 for post-translational control [9].

In hepatocarcinoma, DGAT2 controls the ESRRA-PROX1 transcriptional network to maintain hepatic mitochondrial sustainability [10].

In conclusion, Esrra plays essential roles in various biological processes such as metabolism, autophagy, and cell differentiation. Through gene knockout (KO) and conditional knockout (CKO) mouse models, its functions in diseases like bone deterioration, intestinal inflammation, kidney disease, steatohepatitis, gastric and endometrial cancers, and diabetic kidney injury have been revealed. These findings provide potential therapeutic targets for treating related diseases.

References:

1. Huang, Tongling, Lu, Zhaocheng, Wang, Zihui, Lu, William Weijia, Guan, Min. 2024. Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow. In Nature communications, 15, 3769. doi:10.1038/s41467-024-48255-8. https://pubmed.ncbi.nlm.nih.gov/38704393/

2. Kim, Sup, Lee, June-Young, Shin, Seul Gi, Bae, Jin-Woo, Jo, Eun-Kyeong. 2020. ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota. In Autophagy, 17, 2856-2875. doi:10.1080/15548627.2020.1847460. https://pubmed.ncbi.nlm.nih.gov/33172329/

3. Dhillon, Poonam, Park, Jihwan, Hurtado Del Pozo, Carmen, Montserrat, Nuria, Susztak, Katalin. 2020. The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation. In Cell metabolism, 33, 379-394.e8. doi:10.1016/j.cmet.2020.11.011. https://pubmed.ncbi.nlm.nih.gov/33301705/

4. Tripathi, Madhulika, Gauthier, Karine, Sandireddy, Reddemma, Yen, Paul M, Singh, Brijesh K. 2024. Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting. In Molecular metabolism, 87, 101997. doi:10.1016/j.molmet.2024.101997. https://pubmed.ncbi.nlm.nih.gov/39032642/

5. Li, Feng-Nan, Zhang, Qin-Yi, Li, Ou, Shu, Yi-Jun, Dong, Ping. 2021. ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1. In International journal of biological sciences, 17, 1909-1924. doi:10.7150/ijbs.57623. https://pubmed.ncbi.nlm.nih.gov/34131395/

6. Yang, Keju, Liang, Wei, Hu, Hongtu, Chen, Zhaowei, Ding, Guohua. 2024. ESRRA modulation by empagliflozin mitigates diabetic tubular injury via mitochondrial restoration. In Cellular signalling, 122, 111308. doi:10.1016/j.cellsig.2024.111308. https://pubmed.ncbi.nlm.nih.gov/39059756/

7. Wang, Shufang, Huo, Xinlong. . Comprehensive Analysis of ESRRA in Endometrial Cancer. In Technology in cancer research & treatment, 20, 1533033821992083. doi:10.1177/1533033821992083. https://pubmed.ncbi.nlm.nih.gov/33525981/

8. Tripathi, Madhulika, Gauthier, Karine, Sandireddy, Reddemma, Yen, Paul M, Singh, Brijesh K. 2025. ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation. In Autophagy, , 1-15. doi:10.1080/15548627.2025.2465183. https://pubmed.ncbi.nlm.nih.gov/39936615/

9. Kim, Soo Yeon, Yang, Chul-Su, Lee, Hye-Mi, Giguère, Vincent, Jo, Eun-Kyeong. 2017. ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. In Autophagy, 14, 152-168. doi:10.1080/15548627.2017.1339001. https://pubmed.ncbi.nlm.nih.gov/28841353/

10. Lee, Yoseob, Hwang, Yeseong, Kim, Minki, Fang, Sungsoon, Kim, Jae-Woo. 2024. DGAT2 Plays a Crucial Role to Control ESRRA-PROX1 Transcriptional Network to Maintain Hepatic Mitochondrial Sustainability. In Diabetes & metabolism journal, 48, 901-914. doi:10.4093/dmj.2023.0368. https://pubmed.ncbi.nlm.nih.gov/38644620/