Irf9, also known as interferon regulatory factor 9, 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 [4]. It classically forms the ISGF3 transcription factor complex with STAT1 and STAT2 in response to type I and type III interferons, playing a vital role in innate and adaptive immune responses, inflammation, antiviral response, and cell development [1,3].

In renal fibrosis, myofibroblast-specific deletion of MRTF-A (by cross-breeding Mrtfa-flox mice with Postn-CreERT2 mice) led to the identification of a novel MRTF-A-Zeb1-Irf9 axis. Zeb1, a downstream target of MRTF-A, was found to repress Irf9 transcription. Knockdown of Irf9 overcame the effect of Zeb1 depletion and promoted fibroblast-myofibroblast transition (FMyT), suggesting Irf9's role in renal fibrosis [2]. In osteoporosis, knockdown of Irf9 in an ovariectomized mouse model enhanced osteoclast differentiation. RNA sequencing showed that differentially expressed genes enriched by Irf9 knockdown were related to ferroptosis, and Irf9 knockdown reduced ferroptosis by activating STAT3 to promote osteoclastogenesis [3].

In conclusion, Irf9 is essential in regulating immune responses, cell development, and disease-related processes. Mouse models, such as those used in renal fibrosis and osteoporosis studies, have revealed its role in specific disease conditions. Understanding Irf9's functions provides insights into disease mechanisms and potential therapeutic targets for renal fibrosis, osteoporosis, and other related diseases.

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/