Stat4, short for Signal transducer and activator of transcription 4, is a member of the STAT family of transcription factors. It localizes in the cytoplasm and is phosphorylated when various cytokines bind to the membrane. The dimerized Stat4 then translocates to the nucleus to regulate gene expression. Stat4 is crucial in the Janus kinase (JAK)-STAT signaling pathway, activated by cytokines like IL-12. It plays an essential role in the differentiation and function of multiple immune cells such as natural killer cells, mast cells, dendritic cells, and T helper cells, and is thus of great biological importance in immune responses [2,3,4,8].

Stat4 has been associated with diverse human diseases. In heart failure comorbid with depression, it was identified as one of the hub genes, potentially serving as a diagnostic biomarker and therapeutic target [1]. Genetic polymorphisms in Stat4 strongly influence immune responses, with certain variants associated with altered Stat4 expression/activity, and a close relationship between its polymorphisms and drug efficacy [2]. Altered expression of Stat4, often due to genetic and epigenetic aberrances, has been observed in different tumors and autoimmune diseases, as it can contribute to the pathogenesis of autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and psoriasis [2,4,8]. In prostate cancer, autocrine IL-11 activates the JAK1/Stat4 pathway, leading to docetaxel resistance [7]. In osteoporosis, Stat4 was identified as a gene associated with oxidative stress [5]. In primary glioblastomas, MET overexpression activates the Stat4-PD-L1 signaling, contributing to tumor-associated macrophages-mediated immunosuppression [6].

In summary, Stat4 is a key regulator in the JAK-STAT signaling pathway, essential for immune cell function. Its dysregulation is implicated in numerous diseases including heart failure comorbid with depression, various autoimmune diseases, different types of cancer, and osteoporosis. Studies, although not specified with KO/CKO mouse models in these references, help in understanding its role in disease pathogenesis, potentially guiding the development of targeted therapies for these conditions.