REXO2 is a 3'-to-5' exoribonuclease primarily localized to mitochondria that preferentially degrades short RNA and DNA oligonucleotides (nanoRNA and dinucleotides) 1. The enzyme functions as a homodimer that recognizes the 3'-end nucleobases of substrates through hydrophobic and π-π stacking interactions, requiring magnesium ions for catalysis 1. In mitochondria, REXO2 plays dual roles: 'scavenging' short RNAs produced by the mitochondrial degradosome and clearing RNA processing intermediates to prevent accumulation of double-stranded RNA 2. REXO2 maintains promoter specificity by degrading dinucleotides that otherwise aberrantly stimulate non-specific transcription initiation in mitochondrial DNA 3. Pathologically, REXO2 dysfunction causes interferonopathy; dominant-negative mutations lead to cytosolic accumulation of mitochondrial dsRNA, triggering MDA5-mediated innate immunity and type I interferon responses 4. Clinically, elevated REXO2 expression correlates with poor prognosis in hepatocellular carcinoma and lower-grade glioma, associated with increased tumor cell proliferation and immune infiltration via TNF and NF-κB signaling 56. REXO2 also represents a potential therapeutic target in bladder cancer, where its overexpression associates with metabolic disorders and reduced survival 7.