HELZ2 (helicase with zinc finger 2) is an interferon-stimulated gene encoding a multifunctional RNA-processing enzyme with dual catalytic activities. It contains RNA helicase domains and a 3'-5' exoribonuclease domain, enabling degradation of highly structured RNAs through coordinated ATP-dependent helicase activity and nuclease action with preference for pyrimidine residues 1. Beyond its RNA catalytic functions, HELZ2 acts as a transcriptional coactivator for nuclear receptors including PPARα, PPARγ, and thyroid hormone receptors, interacting with mediator complex components like THRAP3 to enhance ligand-dependent transcriptional activation 2. Clinically, HELZ2 plays diverse roles in disease pathogenesis. It inhibits LINE-1 retrotransposition by degrading L1 RNA and reducing retrotransposition-associated interferon responses 3. In lipid metabolism, HELZ2 directly binds and degrades apoB mRNA through helicase activity, controlling hepatic apoB levels; gain-of-function mutations enhance this activity and protect against atherosclerosis 4. HELZ2 regulates mitochondrial function in diabetic nephropathy via the PPARα-HELZ2-MFN-2 axis 5. Additionally, HELZ2 promotes c-Myc K63-linked polyubiquitination in retinoblastoma tumorigenesis 6, and HELZ2 mutations correlate with endometrial cancer survival 7. These findings establish HELZ2 as a multifunctional regulator with therapeutic potential in cardiovascular, metabolic, and oncologic disease.