ANKRD13D is a ubiquitin-binding protein that specifically recognizes Lys-63-linked polyubiquitin chains and positively regulates ligand-activated EGFR internalization by binding ubiquitinated EGFR at the cell membrane 1. The protein functions as a molecular scaffold that promotes complex formation between activated EGFR and E3 ligases ITCH and RNF11, facilitating receptor sorting for lysosomal degradation 1. ANKRD13D contains ubiquitin-interacting motifs (UIMs) critical for complex assembly with RNF11, with this interaction modulated by EGF stimulation during early endocytosis 1. Beyond EGFR regulation, ANKRD13D demonstrates disease relevance across multiple conditions. In renal cell carcinoma, ANKRD13D is overexpressed primarily in immune cells and positively correlates with Treg cell infiltration and immune checkpoint markers (PDCD1, CTLA4, LAG3), suggesting a role as a key immune regulator 2. Genomic studies identified ANKRD13D associations with arachidonic acid levels in Hispanic American populations, indicating involvement in polyunsaturated fatty acid metabolism 34. In colorectal cancer, ANKRD13D emerged as a prognostic biomarker; knockdown inhibits cell proliferation, migration, and invasion 5. Rare variants in ANKRD13D are associated with Alzheimer's disease risk and neurofibrillary tangle pathology 6. Additionally, ANKRD13D was identified in multiomics analyses of heart failure with reduced ejection fraction 7, suggesting broader cardiac involvement.