DHX9, also known as DExD/H-box helicase 9, is an RNA helicase with crucial roles in multiple biological processes. It is involved in transcription regulation, resolving R-loops, and maintaining genome stability. It participates in pathways such as the interferon-stimulated gene (ISG) expression pathway downstream of type I interferon, and is associated with the hallmarks of cancer, antiviral immunity, and RNA processing [1,2,3]. Genetic models like knockout (KO) mice are valuable for studying its functions.

In myeloid-specific and hepatocyte-specific DHX9 KO mice, DHX9 was confirmed to be crucial for host resistance to RNA virus infections in vivo. It positively regulates ISG expression downstream of type I interferon by directly binding to STAT1 and recruiting Pol II to the ISG promoter region [2]. In mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC), there was an increased susceptibility to experimental colitis, along with a reduction in the numbers of intestinal stem cells (ISCs) and Paneth cells. DHX9 deficiency led to abnormal R-loop accumulation, genomic instability, and a cGAS-STING-mediated inflammatory response, impairing ISC function [4]. In cells expressing a non-phosphorylatable DHX9S321A variant (mimicking a loss-of-function state), there was hypersensitivity to genotoxic stress due to the accumulation of stress-induced R-loops [5].

In summary, DHX9 is essential for maintaining genome stability, host antiviral immunity, and epithelial homeostasis. Studies using KO and conditional KO mouse models have revealed its significance in diseases such as viral infections, inflammatory bowel disease, and potentially in response to genotoxic stress, providing insights into its roles in these biological processes and disease conditions.