KLHDC3 is a substrate-recognition component of the CRL2 E3 ubiquitin ligase complex that mediates protein degradation through the DesCEND (destruction via C-end degrons) pathway 12. The CRL2(KLHDC3) complex specifically recognizes proteins bearing C-terminal degrons—peptide motifs at the extreme C-terminus—particularly those with glycine as the terminal residue and containing preceding arginine residues (e.g., -Arg-(Xaa)n-Arg-Gly, -Arg-(Xaa)n-Lys-Gly motifs) 12. Structurally, KLHDC3 contains a pre-formed pocket within its β-propeller domain that establishes substrate selectivity preferences 3. The complex mediates ubiquitination of truncated selenoproteins (SELENOV, SEPHS2) produced by failed UGA/Sec decoding 4. Clinically, KLHDC3 has emerged as a significant oncoprotein. In non-small cell lung cancer, elevated KLHDC3 expression correlates with worse survival and promotes degradation of the tumor suppressor p14ARF through CUL2-mediated ubiquitination 5. KLHDC3 upregulation contributes to EGFR-targeted drug resistance, suggesting therapeutic potential as a resistance mechanism target 5. In pancreatic cancer, KLHDC3 cooperates with Fbxw7 to promote c-Myc degradation in GSK3-insensitive cells, with KLHDC3 expression associated with patient prognosis in low-SHISA2 tumors 6. Additionally, KLHDC3 loss-of-function rescues proliferation defects in RECQL4-mutant cells by stabilizing truncated RECQL4 variants 7, and rare KLHDC3 variants are associated with familial multiple myeloma 8.