Deciphering the functions of NELL2 in tumorigenesis and beyond

NELL2, a neuron-specific secreted glycoprotein, has emerged as a key regulator in multiple physiological and pathological contexts, including neurodegeneration, immunity, reproduction and cancer. Despite its diverse roles, the context-dependent duality of NELL2-acting as both an oncogene and tumor suppressor, a neuroprotectant and contributor to hyperexcitability-remains mechanistically unclear. Moreover, the tissue-specific signaling cross-talk of NELL2 complicates its therapeutic targeting. Research on NELL2 holds transformative potential for precision medicine, offering insights into cancer therapy, neurodegenerative disease intervention, and infertility treatment, while highlighting the need for mechanistic clarity and context-specific strategies to realize its diagnostic and therapeutic promise. Here, we consolidated research advances of NELL2, delineating its structural features, regulatory networks, and context-dependent roles in neurodegeneration, immunity, reproduction and cancer. By highlighting unresolved mechanistic ambiguities and therapeutic translatability, our work helps to illuminate potential of NELL2 as a diagnostic marker and therapeutic target across diverse diseases.