The NEIL DNA glycosylase family: Molecular mechanisms, disease relevance, and therapeutic potential

Mammalian genomes are continually challenged by endogenous and exogenous stressors that generate oxidative DNA lesions and threaten genome stability, making the base excision repair (BER) pathway indispensable for safeguarding against mutagenesis and cell dysfunction. Within BER cascade, the Nei endonuclease VIII–like (NEIL) glycosylases, including NEIL1, NEIL2, and NEIL3, have evolved as multifunctional, context-dependent regulators: beyond their canonical role of excising oxidized bases, they bridge BER to replication-associated genome maintenance (particularly NEIL1 and NEIL3), transcription-coupled repair (especially NEIL2), mitochondrial homeostasis, chromatin-associated processes, immune modulation, and epigenetic remodeling. In this review, we provide an integrated synthesis of the genomic architecture, structural features, catalytic preferences, and interaction networks of NEIL1–3, and summarize mechanistic and clinical evidence implicating their dysregulation in a broad spectrum of human diseases. We further highlight how altered NEIL expression, genetic variation, and regulatory perturbations shape tumor phenotypes, mutation load, therapy response, and clinical outcomes across diverse cancers, while also influencing neurodegeneration and stroke, cardiovascular injury and atherogenesis, infection-associated inflammation, and systemic autoimmunity. Finally, we discuss translational opportunities centered on NEIL proteins, such as their emerging utility as disease biomarkers and early advances in small-molecule inhibition, and highlight unmet challenges: the need to account for cell-type-specific activity, define safe and effective therapeutic windows, and develop isoform-selective targeting strategies that preserve essential genome surveillance in normal tissues.