DHX58 (DExH-box helicase 58) is a regulatory helicase that modulates innate immune signaling through complex mechanisms involving RNA recognition and protein interactions. As a negative regulator of RIG-I and MDA5-mediated antiviral pathways [UniProt], DHX58 lacks the CARD domain required for direct MAVS/IPS1 activation but can inhibit signaling through competitive binding to viral RNA, suppression of RIG-I dimerization, or interference with IRF3 activation [UniProt]. Conversely, DHX58 demonstrates positive regulatory functions by unwinding viral RNA to facilitate recognition by pattern recognition receptors [UniProt]. The gene is upregulated in M1 macrophages during inflammatory responses 1 and activated by viral and bacterial pathogen-associated molecular patterns 2. Clinically, DHX58 variants influence disease susceptibility and progression. Specific SNPs (rs2074158, rs2074160) associate with chr17 hepatitis C infection in the Chinese Han population, with risk increasing with unfavorable genotype accumulation 3. Conversely, DHX58 correlates with decreased coronary artery disease risk 4. In cancer, MATR3-mediated degradation of DHX58 mRNA suppresses type I interferon signaling, promoting liver cancer progression while reducing anti-tumor immunity 5. DHX58 also mediates retrotransposon-induced interferon responses in Werner syndrome and radiation-induced heart disease 67, suggesting therapeutic potential through modulation of this pathway.