NONO (non-POU domain-containing octamer-binding protein) is a multifunctional nuclear RNA- and DNA-binding protein with broad roles in gene regulation and cellular processes. NONO binds double-stranded DNA at octamer sequences and single-stranded DNA/RNA independently 123. As a heterodimer with SFPQ, NONO regulates pre-mRNA splicing, interacts with U5 snRNA, and forms nuclear paraspeckles with PSPC1 1234. The SFPQ-NONO complex participates in DNA repair mechanisms including non-homologous end joining and V(D)J recombination 5. NONO regulates transcription through promoter binding—for example, the SFPQ-NONO-NR5A1 complex controls CYP17 transcription 6. NONO plays critical roles in innate immunity by assembling into the HDP-RNP complex to facilitate IRF3 phosphorylation and cGAS-STING pathway activation, with differential activation depending on HIV capsid protein interactions 78. In cancer contexts, covalent NONO ligands suppress cancer-relevant transcriptional networks and impair proliferation 9, while NONO regulates alternative splicing affecting redox homeostasis in glioblastoma 10. NONO also regulates vascular inflammation through transcriptional control and enhancer-promoter interactions 1112. In neurodegenerative disease, NONO aggregates accumulate with A-to-I-edited RNAs in Parkinson's disease and dementia with Lewy bodies 13. NONO is essential for spermatogenesis, with RNA-binding defects causing male infertility 14.