Spi1, also known as PU.1, is an E26 transformation-specific sequence-related transcription factor that is pivotal in hematopoiesis, regulating microglial/macrophage commitment and maturation [2]. It is involved in multiple signaling pathways such as the PI3K/AKT/mTOR signaling pathway [2], and is associated with various biological processes including phagocytosis, glycolysis, autophagy, debris clearance, and remyelination [2]. Genetic models like mouse models are valuable for studying its functions.

In multiple disease conditions, Spi1 has been shown to play significant roles. In diabetic myocardial injury, excessive AGEs and copper in diabetes upregulate the ATF3/SPI1/SLC31A1 signaling, disturbing copper homeostasis and promoting cuproptosis [1]. After intracerebral hemorrhage, Spi1 may regulate recovery from neuroinflammation and neurofunctional damage by modulating the microglial/macrophage transcriptome [2]. In gastric cancer, SPI1+CD68+ macrophages may serve as a biomarker for metastasis, and SPI1 promotes M2-type macrophage polarization and angiogenesis [3]. In glioblastoma, SPI1-mediated MIR222HG transcription promotes the proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages [4]. In Alzheimer's disease, Spi1 knockdown in mice exacerbates AD pathology by increasing amyloid-β aggregation and gliosis, while Spi1 overexpression ameliorates these features, suggesting it regulates microglial immune response, complement activation, and phagocytosis [5,7]. In age-related macular degeneration, SPI1-mediated macrophage polarization aggravates the disease [6]. In sepsis, SPI1 enhances monocyte autophagy by inhibiting the transcription of ANXA1 [8]. During endothelial-to-hematopoietic transition from human pluripotent stem cells, SPI1 regulates lineage commitment through the SPI1-KLF1/LYL1 axis [9]. In ankylosing spondylitis, SPI1 regulates the disease progression by modulating TLR5 via the NF-κB signaling pathway [10].

In conclusion, Spi1 is a crucial transcription factor involved in a wide range of biological processes. Studies using gene knockout or conditional knockout mouse models have revealed its significant roles in various disease areas, including diabetes-related myocardial injury, neurodegenerative diseases, cancer, inflammatory diseases, and hematopoietic development. These findings provide valuable insights into the mechanisms of these diseases and potential therapeutic targets related to Spi1.

References:

1. Huo, Shengqi, Wang, Qian, Shi, Wei, Lv, Jiagao, Lin, Li. 2023. ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury. In International journal of molecular sciences, 24, . doi:10.3390/ijms24021667. https://pubmed.ncbi.nlm.nih.gov/36675183/

2. Zhang, Guoqiang, Lu, Jianan, Zheng, Jingwei, Fang, Yuanjian, Yu, Jun. . Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage. In Neural regeneration research, 19, 161-170. doi:10.4103/1673-5374.375343. https://pubmed.ncbi.nlm.nih.gov/37488863/

3. Deng, Guofei, Wang, Pengliang, Su, Rishun, Zhang, Changhua, Yin, Songcheng. 2024. SPI1+CD68+ macrophages as a biomarker for gastric cancer metastasis: a rationale for combined antiangiogenic and immunotherapy strategies. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-009983. https://pubmed.ncbi.nlm.nih.gov/39455096/

4. Fan, Yang, Gao, Zijie, Xu, Jianye, Guo, Xing, Li, Gang. 2023. SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages. In Theranostics, 13, 3310-3329. doi:10.7150/thno.82590. https://pubmed.ncbi.nlm.nih.gov/37351164/

5. Shao, Jie, Youngblood, Hannah, Yang, Luodan. 2025. Targeting SPI1 to mitigate amyloid-β pathology in Alzheimer's disease. In Journal of Alzheimer's disease : JAD, 104, 334-337. doi:10.1177/13872877251316593. https://pubmed.ncbi.nlm.nih.gov/39865683/

6. Qi, Siyi, Zhang, Yihan, Kong, Lingjie, Zhang, Shujie, Zhao, Chen. 2024. SPI1-mediated macrophage polarization aggravates age-related macular degeneration. In Frontiers in immunology, 15, 1421012. doi:10.3389/fimmu.2024.1421012. https://pubmed.ncbi.nlm.nih.gov/38979414/

7. Kim, Byungwook, Dabin, Luke Child, Tate, Mason Douglas, Jucker, Mathias, Kim, Jungsu. 2024. Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis. In Nature communications, 15, 3996. doi:10.1038/s41467-024-48484-x. https://pubmed.ncbi.nlm.nih.gov/38734693/

8. Xie, Wenfeng, Zou, Sainan, Dong, Chengcheng, Yang, Chunhua. 2023. SPI1-mediated autophagy of peripheral blood monocyte cells as a mechanism for sepsis based on single-cell RNA sequencing. In International immunopharmacology, 117, 109909. doi:10.1016/j.intimp.2023.109909. https://pubmed.ncbi.nlm.nih.gov/37012859/

9. Qu, Kengyuan, Mo, Shaokang, Huang, Junfeng, Shen, Jun, Yen, Kuangyu. 2024. SPI1-KLF1/LYL1 axis regulates lineage commitment during endothelial-to-hematopoietic transition from human pluripotent stem cells. In iScience, 27, 110409. doi:10.1016/j.isci.2024.110409. https://pubmed.ncbi.nlm.nih.gov/39108738/

10. Wenbo, Dai, Yifu, He, Li, Kai. 2023. SPI1 Regulates the Progression of Ankylosing Spondylitis by Modulating TLR5 via NF-κB Signaling. In Inflammation, 46, 1697-1708. doi:10.1007/s10753-023-01834-1. https://pubmed.ncbi.nlm.nih.gov/37277671/