The role of NETO2 in neurological disorders and cancer: From molecular function to clinical relevance

Neuropilin and tolloid-like 2 are single-pass transmembrane glycoproteins that were initially identified as auxiliary subunits of kainate receptors in the nervous system. In addition to its role in regulating synaptic transmission and chloride homeostasis, neuropilin and tolloid-like 2 have been implicated in diverse pathological processes. In neurological disorders, such as epilepsy, posttraumatic stress disorder, and chronic pain, decreased neuropilin and tolloid-like 2 expression destabilizes potassium-chloride cotransporter 2 and disrupts the excitatory-inhibitory balance, whereas structural neuropilin and tolloid-like 2 variants have been linked to schizophrenia. Conversely, neuropilin and tolloid-like 2 are markedly upregulated in multiple cancers, including gastric, colorectal, pancreatic, lung, and hepatocellular carcinomas, where they promote proliferation, epithelial-mesenchymal transition, invasion, and drug resistance. Moreover, in gliomas, higher neuropilin and tolloid-like 2 levels correlate with improved patient outcomes, which suggests a context-dependent functional role. These findings indicate that neuropilin and tolloid-like 2 act as diagnostic and prognostic biomarkers and thus can be potential therapeutic targets. This review summarizes the molecular characteristics and physiological functions of neuropilin and tolloid-like 2; its roles in neurological and oncological diseases; and its translational potential in biomarker development, targeted therapy, and precision medicine.