KCMF1 is an E3 ubiquitin ligase that functions as a key component of multiple protein quality control pathways 12. As part of the UBR4-KCMF1 complex, KCMF1 acts downstream of priming ubiquitin ligases to elongate and branch ubiquitin chains on target substrates, particularly K48-linked chains that direct proteasomal degradation 34. The complex recognizes specific N-terminal degrons in unacetylated proteins; N-terminal acetylation shields proteins from KCMF1-mediated degradation 5. KCMF1 participates in the N-end rule pathway and oxidative stress response, where it mediates K63-/K27-linked branched ubiquitin chain assembly on ROS-oxidized proteins for autophagy-mediated degradation 6. Within the SIFI complex, KCMF1 degrades integrated stress response components and unimported mitochondrial precursors to resolve mitochondrial stress 7. Clinically, the UBA6/BIRC6/KCMF1/UBR4 complex is essential for survival of aneuploid epithelial tumors, representing a therapeutic vulnerability through selective ISR activation 89. Additionally, dysregulation of the circHIPK3/miR-346/KCMF1 axis impairs trophoblast function in preeclampsia 10.