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 [4]. Classically, it forms the ISGF3 transcription factor complex with STAT1 and STAT2 in response to type I and type III interferons, playing a significant role in innate and adaptive immune responses, inflammation, antiviral response, and cell development [1,3].

In a study on renal fibrosis, myofibroblast-specific deletion of MRTF-A led to amelioration of fibrosis. RNA-seq identified Zeb1 as a downstream target of MRTF-A, and Zeb1 was found to repress the transcription of Irf9. Knockdown of Irf9 overcame the effect of Zeb1 depletion and promoted fibroblast-myofibroblast transition, suggesting an MRTF-A-ZEB1-IRF9 axis contributing to renal fibrosis [2]. In the context of osteoporosis, knockdown of Irf9 enhanced osteoclast differentiation in vitro, and this was via decreased ferroptosis by activating STAT3 [3]. In melanoma, increased IRF9-STAT2 signaling led to adaptive resistance toward targeted therapy by restraining GSDME-dependent pyroptosis, and knockdown of IRF9 increased sensitivity to BRAF inhibitors [5].

In conclusion, Irf9 is essential in multiple biological processes and disease conditions. Gene-knockout and conditional-knockout mouse models have revealed its role in renal fibrosis, osteoporosis, and melanoma, among others. Understanding Irf9 function through these models provides insights into disease mechanisms and potential therapeutic targets.