STAT4, Signal transducer and activator of transcription 4, is a member of the STAT family. It localizes to the cytoplasm, gets phosphorylated after cytokine-membrane binding, dimerizes, and translocates to the nucleus to regulate gene expression. STAT4 is activated by IL-12 binding to its receptor and is involved in the Janus kinase (JAK)-STAT signaling pathway, playing a crucial role in immune responses, especially in the differentiation and function of immune cells such as natural killer cells, mast cells, dendritic cells, and T helper cells [2,3,4].

STAT4 has been associated with multiple diseases. In heart failure comorbid with depression, STAT4, along with other genes, may be a potential diagnostic biomarker and therapeutic target [1]. Genetic polymorphisms in STAT4 influence immune responses and disease outcomes, especially in cancer and autoimmune diseases [2]. Altered STAT4 expression, often due to genetic and epigenetic aberrances, has been observed in different tumors and autoimmune diseases [4]. In osteoporosis, STAT4 may be part of the Palbociclib/miR-141-3p/STAT4 axis related to oxidative stress [5]. In primary glioblastomas, the MET-STAT4-PD-L1 axis may contribute to immune evasion and poor prognosis [6]. In prostate cancer, the JAK1/STAT4 pathway can lead to docetaxel resistance via autocrine IL11-mediated mechanisms [7]. In systemic lupus erythematosus, the IL-12-STAT4 axis may contribute to autoantibody generation [8].

In conclusion, STAT4 is a key regulator in the JAK-STAT signaling pathway, essential for immune cell function. Its dysregulation is implicated in various diseases including heart-depression comorbidity, cancer, autoimmune diseases, osteoporosis, and glioblastomas. Studies on STAT4 contribute to understanding disease mechanisms and may offer potential therapeutic strategies.

References:

1. Huang, Kai, Zhang, Xinying, Duan, Jiahao, Yang, Chun, Yang, Ling. 2022. STAT4 and COL1A2 are potential diagnostic biomarkers and therapeutic targets for heart failure comorbided with depression. In Brain research bulletin, 184, 68-75. doi:10.1016/j.brainresbull.2022.03.014. https://pubmed.ncbi.nlm.nih.gov/35367598/

2. Xia, Yan, Xie, Yanni, Zhang, Hao, Liu, Lunzhi. 2024. STAT4 gene polymorphisms in human diseases. In Frontiers in immunology, 15, 1479418. doi:10.3389/fimmu.2024.1479418. https://pubmed.ncbi.nlm.nih.gov/39575235/

3. Yang, Chou, Mai, Haoming, Peng, Jinxin, Hou, Jinlin, Jiang, Deke. 2020. STAT4: an immunoregulator contributing to diverse human diseases. In International journal of biological sciences, 16, 1575-1585. doi:10.7150/ijbs.41852. https://pubmed.ncbi.nlm.nih.gov/32226303/

4. Tolomeo, Manlio, Cascio, Antonio. 2024. STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases. In International reviews of immunology, 43, 394-418. doi:10.1080/08830185.2024.2395274. https://pubmed.ncbi.nlm.nih.gov/39188021/

5. Ji, Jiajia, Wu, Shaobo, Bao, Xueyuan, Hao, Dingjun, Huang, Dageng. 2023. Mediating oxidative stress through the Palbociclib/miR-141-3p/STAT4 axis in osteoporosis: a bioinformatics and experimental validation study. In Scientific reports, 13, 19560. doi:10.1038/s41598-023-46813-6. https://pubmed.ncbi.nlm.nih.gov/37949959/

6. Wang, Qiang-Wei, Sun, Li-Hua, Zhang, Ying, Jiang, Tao, Bao, Zhao-Shi. . MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas. In Journal for immunotherapy of cancer, 9, . doi:10.1136/jitc-2021-002451. https://pubmed.ncbi.nlm.nih.gov/34667077/

7. Cheng, Bisheng, Li, Lingfeng, Luo, Tianlong, Lai, Yiming, Huang, Hai. 2024. Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway. In Journal of experimental & clinical cancer research : CR, 43, 67. doi:10.1186/s13046-024-02962-8. https://pubmed.ncbi.nlm.nih.gov/38429845/

8. Ueno, Hideki. 2019. The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus. In European journal of immunology, 50, 10-16. doi:10.1002/eji.201948134. https://pubmed.ncbi.nlm.nih.gov/31762023/