MYCBP2, also known as PAM or Phr1, is an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub. It is involved in diverse processes such as neuronal connectivity, synaptic growth, cell division, neuronal survival, and protein ubiquitination. It participates in pathways related to axon development, immune response regulation, and lipid metabolism, and is of great biological importance [1,4,5]. Genetic models like Caenorhabditis elegans are valuable for studying MYCBP2.

Loss-of-function variants in MYCBP2 in patients lead to neurobehavioural phenotypes and corpus callosum defects. Nuclease technology-mediated introduction of disease-associated variants into the C. elegans MYCBP2 orthologue, RPM-1, showed axonal and behavioural abnormalities, suggesting MYCBP2 variants likely result in loss of function [1]. In spinal cord injury, MYCBP2 delivered via ginsenoside Rg1-pretreated neuronal cell-derived extracellular vesicles promotes microglial M2-phenotype polarization and reduces oxidative stress, thus enhancing neurological recovery [2]. In thyroid cancer, high MYCBP2 expression is associated with increased infiltration of immune cells, better prognosis, and higher sensitivity to immunotherapy, suggesting it may be a predictive biomarker for immune checkpoint inhibitor efficacy [3]. In MASH-associated hepatocellular carcinoma, MYCBP2 acts as a potential tumor suppressor by modulating lipid metabolism through promoting the ubiquitination and degradation of HNF4α [4]. In breast cancer, dysregulation of MYCBP2 is accompanied by decreased disease-free survival, and its loss confers resistance to apoptosis from cisplatin-induced DNA damage [6].

In conclusion, MYCBP2 is crucial for normal biological functions, especially in neural development, immune response, and cancer-related processes. Studies using model organisms and patient-derived data have revealed its role in various disease conditions, including neurodevelopmental disorders, spinal cord injury, thyroid cancer, hepatocellular carcinoma, and breast cancer. These findings provide insights into potential therapeutic targets related to MYCBP2-associated pathways.