DHX9 (DExH-box helicase 9) is an RNA/DNA helicase with multifaceted roles in nuclear and cytoplasmic processes. Its primary function involves unwinding double-stranded RNA and DNA structures through ATP-dependent hydrolysis 1. Mechanistically, DHX9 contains two N-terminal double-stranded RNA-binding domains and functions in transcription regulation, R-loop metabolism, and RNA processing 12. In R-loop regulation, DHX9 acts bidirectionally—promoting both formation and resolution—with SUMOylation at lysine 120 critical for stabilizing protein interactions necessary for R-loop resolution 3. DHX9 regulates circRNA biogenesis through RNA helicase activity and controls miRNA maturation pathways 4. Disease relevance extends beyond its classical viral roles to neurodevelopmental disorders and Charcot-Marie-Tooth disease, with monoallelic variants causing phenotypes ranging from mild developmental delay to polyneuropathy; missense variants affecting the nuclear localization signal cause cytoplasmic accumulation and severe phenotypes, while variants increasing R-loop levels drive genomic instability 5. Clinically, DHX9 emerges as a therapeutic target in cancer: its depletion in small cell lung cancer triggers innate immunity through dsRNA and R-loop accumulation, sensitizing tumors to immunotherapy 6. Similarly, DHX9 inhibition combined with ATR inhibition induces replication stress in ovarian cancer 7. These findings establish DHX9 as a critical genome guardian with broad implications for cancer immunotherapy and neurodevelopmental disease.