MKRN1 (makorin ring finger protein 1) is an E3 ubiquitin ligase that catalyzes ubiquitination of diverse protein substrates, with critical roles in cell survival, apoptosis, and tumor progression 1. Under normal conditions, MKRN1 suppresses p53-dependent apoptosis; however, under stress it promotes apoptosis by repressing p21/CDKN1A 1. MKRN1 mediates ubiquitination and proteasomal degradation of multiple substrates including p14ARF, AGC1, SNIP1, and SOX15, with substrate specificity regulated by alternative splicing and RNA-binding capacity 2345. In cancer, MKRN1 overexpression promotes malignant phenotypes across multiple tumor types. In colorectal cancer, MKRN1 activates TGF-β signaling by degrading SNIP1, inducing epithelial-mesenchymal transition and metastasis 4. MKRN1 also confers oxaliplatin resistance by degrading the mitochondrial transporter AGC1, reprogramming cellular metabolism and antioxidant responses 3. In triple-negative breast cancer, SF3A2-regulated alternative splicing generates an oncogenic MKRN1 isoform promoting cisplatin resistance 6. In glioblastoma, circVPS8 scaffolds MKRN1 to regulate ferroptosis through SOX15 and HNF4A degradation 5. Therapeutically, MKRN1 inhibition via ebastine destabilization protects against metabolic dysfunction-associated steatohepatitis 7. These findings establish MKRN1 as a pivotal oncogenic E3 ligase and therapeutic target across multiple disease contexts.