Sat1, also known as spermidine/spermine N1-acetyltransferase 1, is a rate-limiting enzyme in polyamine catabolism. It is critically involved in converting spermidine and spermine back to putrescine. The gene participates in polyamine metabolism and is associated with pathways like ferroptosis, which is a form of regulated cell death. Understanding Sat1 is crucial as it impacts various biological processes and disease conditions [1,2,3,4,7,9].

In several disease models, the role of Sat1 has been revealed. In triple-negative breast cancer, high SAT1 expression is associated with poor prognoses, and SAT1 knockdown inhibits cell proliferation and migration, suggesting it drives tumor progression through the SAT1/YBX1/mTOR axis [5]. In an osteoporosis murine model, osteoclasts express a high level of SAT1 during osteoclastogenesis, and targeting SAT1 with Berenil promotes osteoclast apoptosis, reversing bone loss [6]. In X-linked childhood-onset systemic lupus erythematosus, loss-of-function variants in SAT1 were identified in affected families, and Sat1 p.Glu92Leufs*6 KI mice spontaneously developed lupus-like symptoms, highlighting the pathogenic role of dysregulated polyamine catabolism [8].

In conclusion, Sat1 plays essential roles in polyamine metabolism and is implicated in multiple disease conditions such as cancer, osteoporosis, and lupus. Gene-knockout and knock-in mouse models have been instrumental in uncovering its functions in these diseases, providing potential therapeutic targets for treatment.

References:

1. Ou, Yang, Wang, Shang-Jui, Li, Dawei, Chu, Bo, Gu, Wei. 2016. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. In Proceedings of the National Academy of Sciences of the United States of America, 113, E6806-E6812. doi:. https://pubmed.ncbi.nlm.nih.gov/27698118/

2. Murthy, Divya, Attri, Kuldeep S, Shukla, Surendra K, Wellen, Kathryn E, Singh, Pankaj K. 2024. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. In Nature cell biology, 26, 613-627. doi:10.1038/s41556-024-01372-4. https://pubmed.ncbi.nlm.nih.gov/38429478/

3. Wan, Kexing, Jia, Min, Zhang, Hong, Liu, Yongmin, Li, Man. 2023. Electroacupuncture Alleviates Neuropathic Pain by Suppressing Ferroptosis in Dorsal Root Ganglion via SAT1/ALOX15 Signaling. In Molecular neurobiology, 60, 6121-6132. doi:10.1007/s12035-023-03463-z. https://pubmed.ncbi.nlm.nih.gov/37421564/

4. Dang, Yini, He, Qing, Yang, Siyu, Zheng, Yu, Wu, Ting. 2022. FTH1- and SAT1-Induced Astrocytic Ferroptosis Is Involved in Alzheimer's Disease: Evidence from Single-Cell Transcriptomic Analysis. In Pharmaceuticals (Basel, Switzerland), 15, . doi:10.3390/ph15101177. https://pubmed.ncbi.nlm.nih.gov/36297287/

5. Tian, Wenwen, Zhu, Lewei, Luo, Yongzhou, Xie, Xiaoming, Ye, Feng. 2024. Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple-Negative Breast Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2309903. doi:10.1002/advs.202309903. https://pubmed.ncbi.nlm.nih.gov/39073262/

6. Jin, Zhichun, Xu, Hao, Sun, Xueyu, Yan, Bin, Wang, Lin. 2024. Targeting SAT1 prevents osteoporosis through promoting osteoclast apoptosis. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 175, 116732. doi:10.1016/j.biopha.2024.116732. https://pubmed.ncbi.nlm.nih.gov/38739990/

7. Yang, Huihuang, Li, Yingmin, Zhu, Weihao, Cong, Bin, Shi, Weibo. 2024. SAT1/ALOX15 Signaling Pathway Is Involved in Ferroptosis After Skeletal Muscle Contusion. In International journal of molecular sciences, 25, . doi:10.3390/ijms252011317. https://pubmed.ncbi.nlm.nih.gov/39457099/

8. Xu, Lingxiao, Zhao, Jian, Sun, Qing, Gilkeson, Gary S, Tsao, Betty P. 2022. Loss-of-function variants in SAT1 cause X-linked childhood-onset systemic lupus erythematosus. In Annals of the rheumatic diseases, 81, 1712-1721. doi:10.1136/ard-2022-222795. https://pubmed.ncbi.nlm.nih.gov/35977808/

9. Xu, Jingting, Ruan, Zhaoxuan, Guo, Zhou, Sun, Kai, Guo, Fengjing. 2024. Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway. In Bone & joint research, 13, 110-123. doi:10.1302/2046-3758.133.BJR-2023-0250.R1. https://pubmed.ncbi.nlm.nih.gov/38447596/