TRIM15 is an E3 ubiquitin ligase that regulates multiple cellular processes through K63-linked polyubiquitination of signaling proteins. Functionally, TRIM15 promotes ERK1/2 activation by facilitating K63-linked ubiquitination, enhancing their interaction with MEK 1. Beyond canonical signaling, TRIM15 modulates diverse pathways: it mediates K63 ubiquitination of AKT to activate proliferative signaling 2, disrupts Axin1 polymerization to promote Wnt/β-catenin signaling 3, and degrades Keap1 to stabilize the antioxidant transcription factor Nrf2 4. In disease contexts, TRIM15 overexpression drives progression across multiple cancer types including melanoma, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, colorectal cancer, and lung cancer 156234. Notably, TRIM15 also promotes chondrocyte senescence and osteoarthritis through K48-linked YAP ubiquitination 7. Clinical significance is substantial: high TRIM15 expression correlates with poor prognosis in multiple cancers and mediates therapeutic resistance to tyrosine kinase inhibitors in hepatocellular carcinoma 5. Targeting TRIM15 emerges as a promising therapeutic strategy across multiple malignancies and degenerative diseases.