NEIL3 (nei like DNA glycosylase 3) is a base excision repair enzyme that preferentially recognizes single-stranded DNA (ssDNA) and partially ssDNA structures over double-stranded DNA 1234. The protein functions as a monofunctional DNA glycosylase 4, efficiently removing oxidative lesions including spiroiminodihydantoin (Sp), guanidinohydantoin (Gh), 5-hydroxyuracil, and thymine glycol by cleaving N-glycosyl bonds 345. NEIL3 plays a specialized role in interstrand cross-link (ICL) repair by cleaving one strand of covalently linked lesions without generating double-strand breaks 67. During DNA replication, NEIL3 acts preferentially on damage within single-stranded regions and fork structures, complementing NEIL1's double-stranded DNA activity 5. In neonatal tissues, NEIL3 appears to be the primary enzyme removing Sp and Gh lesions from ssDNA 4. NEIL3 expression is induced by oxidative and inflammatory stress, with regulation potentially involving G-quadruplex formation at its promoter 8. Beyond its canonical DNA repair function, circNEIL3 (a circular RNA) promotes glioma progression by stabilizing the oncogenic protein IGF2BP3 and mediating macrophage immunosuppressive polarization 9, suggesting NEIL3-derived non-coding RNAs may contribute to cancer pathogenesis.