Irf9, an interferon regulatory factor, is a crucial transcription factor. It mediates the expression of interferon-stimulated genes (ISGs) via the Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway, playing a major role in innate and adaptive immune responses, inflammation, antiviral response, and cell development [4,3]. Classically, it forms the ISGF3 transcription factor complex with STAT1 and STAT2 in response to type I and type III interferons [1].

In the context of renal fibrosis, a myofibroblast-specific deletion of MRTF-A (achieved through cross-breeding Mrtfa-flox mice with Postn-CreERT2 mice) led to amelioration of renal fibrosis. Transcriptomic assays showed that Zeb1, a downstream target of MRTF-A, might contribute to fibroblast-myofibroblast transition (FMyT) by repressing Irf9 transcription. Irf9 knockdown promoted FMyT, while its overexpression antagonized TGF-β-induced FMyT, unveiling an MRTF-A-Zeb1-Irf9 axis in renal fibrosis [2]. In osteoporosis, knockdown of Irf9 in an ovariectomized mouse model enhanced osteoclast differentiation via decreased ferroptosis by activating STAT3 [3]. In common carp, overexpression of Irf9 in CCF cells reduced CyHV-3 replication by upregulating Mx1 via the PI3K-AKT signalling pathway [5].

In conclusion, Irf9 is essential in regulating multiple biological processes. Studies using gene knockout or conditional knockout mouse models have revealed its significant roles in diseases such as renal fibrosis, osteoporosis, and viral infections in fish. These findings contribute to understanding the molecular mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Fink, Karin, Grandvaux, Nathalie. 2013. STAT2 and IRF9: Beyond ISGF3. In JAK-STAT, 2, e27521. doi:10.4161/jkst.27521. https://pubmed.ncbi.nlm.nih.gov/24498542/

2. Zhao, Qianwen, Shao, Tinghui, Zhu, Yuwen, Wu, Xiaoyan, Zhang, Tao. 2023. An MRTF-A-ZEB1-IRF9 axis contributes to fibroblast-myofibroblast transition and renal fibrosis. In Experimental & molecular medicine, 55, 987-998. doi:10.1038/s12276-023-00990-6. https://pubmed.ncbi.nlm.nih.gov/37121967/

3. Lan, Chao, Zhou, Xuan, Shen, Ximei, Zheng, Lifeng, Yan, Sunjie. 2023. Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation. In Inflammation, 47, 99-113. doi:10.1007/s10753-023-01896-1. https://pubmed.ncbi.nlm.nih.gov/37804406/

4. Paul, Alvin, Ismail, Mohd Nazri, Tang, Thean Hock, Ng, Siew Kit. 2023. Phosphorylation of interferon regulatory factor 9 (IRF9). In Molecular biology reports, 50, 3909-3917. doi:10.1007/s11033-023-08253-3. https://pubmed.ncbi.nlm.nih.gov/36662450/

5. Jiang, Xiaona, Ren, Wanying, Tian, Lijing, Shi, Lianyu, Jia, Zhiying. 2023. IRF9 inhibits CyHV-3 replication by regulating the PI3K-AKT signalling pathway in common carp (Cyprinus carpio) epithelial cells. In Developmental and comparative immunology, 148, 104905. doi:10.1016/j.dci.2023.104905. https://pubmed.ncbi.nlm.nih.gov/37549834/