Sesn3, also known as Sestrin 3, belongs to a small protein-coding gene family. It has been implicated in multiple biological processes such as anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. It is also involved in pathways like the hedgehog pathway, IL6-Stat3, Akt, and mTOR signaling cascades, which are crucial for normal cellular functions and disease-related processes [1,2,3,4,5]. Genetic models, especially gene knockout (KO) mouse models, have been valuable in studying Sesn3's functions.

In a Sesn3 knockout mouse model, when induced with carcinogens, these mice developed more severe hepatocellular carcinoma (HCC) compared to wild-type mice. They had higher levels of alpha-fetoprotein, arginase 1, and cytokeratin 19, as well as higher metastatic rates. Histological and signaling analyses showed elevated extracellular matrix and cancer stem cell markers, and activated IL6-Stat3 and Akt pathways. Biochemical and microscopic analyses revealed that Sesn3 inhibits Gli2, a downstream transcription factor of the hedgehog signaling, and in Sesn3-deficient liver tissue, Gli2-regulated genes Pdgfrb and Cd44 were upregulated. This indicates that Sesn3 plays a critical tumor-suppressor role in the liver, at least partly through the inhibition of the hedgehog signaling [1].

In conclusion, Sesn3 is a key gene involved in multiple biological processes. The Sesn3 KO mouse model has been instrumental in revealing its tumor-suppressor role in liver cancer, highlighting its importance in understanding the pathogenesis of HCC and potentially providing new insights for cancer treatment strategies.

References:

1. Liu, Yunjian, Kim, Hyeong Geug, Dong, Edward, Liangpunsakul, Suthat, Dong, Xiaocheng Charlie. 2019. Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway. In Biochimica et biophysica acta. Molecular basis of disease, 1865, 2685-2693. doi:10.1016/j.bbadis.2019.07.011. https://pubmed.ncbi.nlm.nih.gov/31351129/

2. Chen, Qiusan, Zhong, Guoqiang, Fang, Xianmei, Wang, Shanping, Li, Mingsong. 2025. The multifaceted role of Sestrin 3 (SESN3) in oxidative stress, inflammation and tumorigenesis. In Biochimica et biophysica acta. Molecular cell research, 1872, 119938. doi:10.1016/j.bbamcr.2025.119938. https://pubmed.ncbi.nlm.nih.gov/40174866/

3. Miki, Yasuo, Tanji, Kunikazu, Mori, Fumiaki, Takahashi, Hitoshi, Wakabayashi, Koichi. 2018. Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging. In Neuroscience letters, 684, 35-41. doi:10.1016/j.neulet.2018.06.052. https://pubmed.ncbi.nlm.nih.gov/29966750/

4. Han, Xiao, Yang, Yang, Liu, Sujuan, Shao, Heng, Fu, Li. 2022. Aerobic exercise ameliorates insulin resistance in C57BL/6 J mice via activating Sestrin3. In Biochimica et biophysica acta. Molecular basis of disease, 1869, 166568. doi:10.1016/j.bbadis.2022.166568. https://pubmed.ncbi.nlm.nih.gov/36220588/

5. Vakana, Eliza, Arslan, Ahmet Dirim, Szilard, Amy, Altman, Jessica K, Platanias, Leonidas C. 2013. Regulatory effects of sestrin 3 (SESN3) in BCR-ABL expressing cells. In PloS one, 8, e78780. doi:10.1371/journal.pone.0078780. https://pubmed.ncbi.nlm.nih.gov/24260131/