Stat3, short for signal transducer and activator of transcription 3, is a nuclear transcription factor that is a key member of the JAK/STAT signaling pathway [1-4, 6-7, 10]. It regulates genes involved in cell cycle, cell survival, and immune response [4]. In normal cells, Stat3 is tightly regulated to maintain a transiently active state, but persistent activation is frequently seen in cancers [6].

Stat3 has been found to be broadly hyperactivated in both cancer and non-cancerous cells within the tumor ecosystem, playing important roles in inhibiting immune activation regulators and promoting immunosuppressive factors, making it a promising target for cancer immunotherapy [1]. In breast cancer, overexpressed and constitutively activated Stat3 is involved in progression, proliferation, metastasis, and chemoresistance [3]. In pancreatic cancer, Stat3 binds to the GPX4 promoter region to promote its transcription, and disruption of this STAT3/GPX4 signalling by thiostrepton can induce ferroptosis [5]. In liver fibrosis, Stat3 activation can have anti-or pro-inflammatory roles [2]. In kidney disease, dysregulated Stat3 activation has a detrimental role, and genetic knockout and manipulation studies have shown benefits of inhibiting its activity, though pharmacological inhibition has not yet reached the clinical forefront [7].

In conclusion, Stat3 is a crucial regulator in multiple biological processes and diseases. Model-based research, especially gene knockout and manipulation studies, has revealed its significant roles in cancer, liver fibrosis, and kidney disease. These findings provide insights into potential therapeutic strategies targeting Stat3 in these disease areas.

References:

1. Zou, Sailan, Tong, Qiyu, Liu, Bowen, Tian, Yan, Fu, Xianghui. 2020. Targeting STAT3 in Cancer Immunotherapy. In Molecular cancer, 19, 145. doi:10.1186/s12943-020-01258-7. https://pubmed.ncbi.nlm.nih.gov/32972405/

2. Zhao, Jie, Qi, Yong-Fen, Yu, Yan-Rong. 2020. STAT3: A key regulator in liver fibrosis. In Annals of hepatology, 21, 100224. doi:10.1016/j.aohep.2020.06.010. https://pubmed.ncbi.nlm.nih.gov/32702499/

3. Ma, Jia-Hui, Qin, Li, Li, Xia. 2020. Role of STAT3 signaling pathway in breast cancer. In Cell communication and signaling : CCS, 18, 33. doi:10.1186/s12964-020-0527-z. https://pubmed.ncbi.nlm.nih.gov/32111215/

4. Butturini, Elena, Carcereri de Prati, Alessandra, Mariotto, Sofia. 2020. Redox Regulation of STAT1 and STAT3 Signaling. In International journal of molecular sciences, 21, . doi:10.3390/ijms21197034. https://pubmed.ncbi.nlm.nih.gov/32987855/

5. Zhang, Weifan, Gong, Mengyuan, Zhang, Wunai, Ma, Qingyong, Wang, Zheng. 2022. Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. In Cell death & disease, 13, 630. doi:10.1038/s41419-022-05082-3. https://pubmed.ncbi.nlm.nih.gov/35859150/

6. Dong, Jinyun, Cheng, Xiang-Dong, Zhang, Wei-Dong, Qin, Jiang-Jiang. 2021. Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation. In Journal of medicinal chemistry, 64, 8884-8915. doi:10.1021/acs.jmedchem.1c00629. https://pubmed.ncbi.nlm.nih.gov/34170703/

7. Pace, Jesse, Paladugu, Praharshasai, Das, Bhaskar, He, John C, Mallipattu, Sandeep K. 2019. Targeting STAT3 signaling in kidney disease. In American journal of physiology. Renal physiology, 316, F1151-F1161. doi:10.1152/ajprenal.00034.2019. https://pubmed.ncbi.nlm.nih.gov/30943069/