DNASE2 encodes a lysosomal acid deoxyribonuclease that hydrolyzes double-stranded DNA under acidic conditions. It plays a central role in clearing nucleic acids generated during apoptosis, thereby preventing autoinflammation. DNASE2 is essential for fetal development and definitive erythropoiesis, where it degrades nuclear DNA expelled from erythroid precursor cells during their maturation. Biochemically, DNASE2 operates optimally at pH 5.1–5.3 and does not require divalent cations for activity. It preferentially cleaves native DNA approximately 5–15 times faster than denatured DNA, generating 3′-phosphoryl and 5′-hydroxyl terminated fragments. The enzyme is ubiquitously expressed across tissues and body fluids 1. Loss-of-function mutations in DNASE2 cause monogenic lupus characterized by early-onset systemic lupus erythematosus features, including polyarthritis, erythematous rash, glomerulonephritis, and neurological involvement 2. DNASE2 deficiency also associates with hematologic disorders including autoinflammatory-pancytopenia syndrome and sideroblastic anemia. These disease manifestations reflect impaired clearance of apoptotic DNA, triggering pathogenic autoimmune responses. The therapeutic potential of DNASE2 has been explored in cancer contexts, where transgenic expression of recombinant DNASE2 selectively eradicates ovarian cancer cells when targeted via EGFR-driven expression systems 3.