DNASE1L2 is a divalent cation-dependent endonuclease primarily involved in nuclear DNA degradation during epidermal keratinocyte differentiation and corneocyte formation 1. The enzyme is preferentially expressed in the epidermis, with protein abundance in the stratum granulosum correlating with terminal differentiation 1. DNASE1L2 exhibits a distinctive low pH optimum and was evolutionarily acquired in amniotes as an adaptation to terrestrial life 2. Beyond skin homeostasis, DNASE1L2 contributes to innate immune defense by degrading extracellular DNA and suppressing bacterial biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus 3. The enzyme is actin-resistant compared to DNase1, making it suitable for cystic fibrosis lung disease treatment, where it effectively reduces mucus viscosity enriched with DNA and actin 4. Disease relevance includes downregulation in vesicular hand eczema, suggesting aberrant epidermal differentiation 5, and elevated expression in breast cancer where it promotes epithelial-mesenchymal transition and predicts poor prognosis 6. Additionally, DNASE1L2 shows protective effects against cataract development 7. DNase1L2 cooperates with Trex2 nuclease in cornification-associated DNA breakdown, particularly in oral epithelia 8.