PIAS3, short for Protein Inhibitor of Activated STAT3, is a key regulator in multiple biological processes. It functions as a SUMO E3 ligase and is involved in regulating signal transduction pathways, especially those related to STAT3, TGF-β, and NF-κB. PIAS3 is important in maintaining cellular homeostasis, and its dysregulation is associated with various diseases [1,3,4,5,6]. Genetic models, such as KO or CKO mouse models, can provide insights into its in-vivo functions.

In hepatocellular carcinoma, PIAS3 promotes ferroptosis by regulating TXNIP via the TGF-β signaling pathway [1]. In myocardial ischemia/reperfusion injury, zinc deficiency leads to ubiquitination and degradation of PIAS3, which in turn alleviates injury by activating STAT3 to promote ZIP family zinc transporter gene expression [2]. In hepatocellular cancer cells, oxidative stress represses PIAS3 expression, leading to STAT3 activation and changes in cell behavior [3]. In chronic colitis-associated malignant transformation, PIAS3-mediated feedback loops control cell proliferation [4]. In psoriasis, low PIAS3 expression in psoriatic lesions is associated with disease pathogenesis, and PIAS3 can regulate the STAT3/NF-κB signaling pathway [5]. In an Alzheimer's disease cell model, reduced PIAS3 expression is observed, and its overexpression can reverse detrimental effects [6].

In conclusion, PIAS3 plays essential roles in various biological processes and diseases. Studies using KO/CKO mouse models could potentially further clarify its functions in these contexts, especially in diseases like cancer, ischemia/reperfusion injury, psoriasis, and Alzheimer's disease. Understanding PIAS3 is crucial for uncovering disease mechanisms and developing new therapeutic strategies.

References:

1. Bao, Wenfang, Wang, Jialin, Fan, Kailing, Gao, Yong, Chen, Jingde. 2023. PIAS3 promotes ferroptosis by regulating TXNIP via TGF-β signaling pathway in hepatocellular carcinoma. In Pharmacological research, 196, 106915. doi:10.1016/j.phrs.2023.106915. https://pubmed.ncbi.nlm.nih.gov/37689128/

2. Zhao, Huanhuan, Liu, Dan, Sun, Sha, Yu, Yonghao, Xu, Zhelong. 2024. PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury. In Free radical biology & medicine, 221, 188-202. doi:10.1016/j.freeradbiomed.2024.05.025. https://pubmed.ncbi.nlm.nih.gov/38750767/

3. Sun, Honghua, Li, Yanglong, Quan, Xianglan, Jin, Yongmin, Shen, Xionghu. 2021. PIAS3/SOCS1-STAT3 axis responses to oxidative stress in hepatocellular cancer cells. In American journal of translational research, 13, 12395-12409. doi:. https://pubmed.ncbi.nlm.nih.gov/34956461/

4. Ma, Junting, Yang, Yaping, Fu, Yong, Zhang, Junfeng, Chen, Jiangning. 2018. PIAS3-mediated feedback loops promote chronic colitis-associated malignant transformation. In Theranostics, 8, 3022-3037. doi:10.7150/thno.23046. https://pubmed.ncbi.nlm.nih.gov/29896300/

5. Zhou, Jing, Bian, Huiying, Wu, Nan. 2023. Protein inhibitor of activated STAT3 (PIAS3) attenuates psoriasis and associated inflammation. In The Journal of dermatology, 50, 1262-1271. doi:10.1111/1346-8138.16874. https://pubmed.ncbi.nlm.nih.gov/37392066/

6. Li, Chen, Wang, Ruili, Zhang, Youyou, Hu, Chunting, Ma, Qiaoya. 2021. PIAS3 suppresses damage in an Alzheimer's disease cell model by inducing the STAT3-associated STAT3/Nestin/Nrf2/HO-1 pathway. In Molecular medicine (Cambridge, Mass.), 27, 150. doi:10.1186/s10020-021-00410-3. https://pubmed.ncbi.nlm.nih.gov/34837964/