Spi1, also known as PU.1, is an E26 transformation-specific sequence-related transcription factor that plays a vital role in hematopoiesis, regulating cell lineage commitment such as during endothelial-to-hematopoietic transition [9]. It is also involved in many other biological processes, including the regulation of the microglial/macrophage inflammatory response and autophagy, and is associated with various signaling pathways like PI3K/AKT/mTOR [2].

In multiple disease models, Spi1 has been shown to have significant impacts. In Alzheimer's disease mouse models, Spi1 knockdown exacerbates amyloid-β aggregation and gliosis, while overexpression ameliorates these features, suggesting its role in regulating immune response pathways and the complement system [5,7]. In intracerebral hemorrhage, Spi1 may regulate recovery from neuroinflammation and neurofunctional damage by modulating the microglial/macrophage transcriptome [2]. In age-related macular degeneration, Spi1-mediated macrophage polarization aggravates the disease, and its suppression can inhibit M1 polarization and attenuate neovascularization [6]. In gastric cancer, SPI1 + CD68+ macrophages are a biomarker for metastasis, and SPI1 promotes M2-type macrophage polarization and angiogenesis [3]. In glioblastoma, SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages [4]. In sepsis, SPI1 enhances monocyte autophagy by inhibiting ANXA1 transcription [8]. In diabetic myocardial injury, excessive AGEs and copper upregulate the ATF3/SPI1/SLC31A1 signaling, promoting cuproptosis [1].

In conclusion, Spi1 is a crucial transcription factor involved in diverse biological functions, especially in processes related to the immune response and cell fate determination. Through gene-knockout or over-expression mouse models, its role in various diseases such as Alzheimer's disease, intracerebral hemorrhage, age-related macular degeneration, gastric cancer, glioblastoma, sepsis, and diabetic myocardial injury has been revealed, providing potential therapeutic targets for these diseases.