KLHDC2 (kelch domain containing 2) functions as a substrate-recognition component of a Cullin-RING E3 ubiquitin ligase complex (CRL2) that mediates protein degradation through the DesCEND (destruction via C-end degrons) pathway 1. The primary mechanism involves specific recognition of proteins containing C-terminal diglycine (Gly-Gly) degrons, leading to their ubiquitination and subsequent proteasomal degradation 12. KLHDC2 exhibits sophisticated autoregulation through interconversion between self-inactivated homotetramers and active monomeric forms, where its own C-terminal Gly-Ser motif mimics a degron to prevent promiscuous substrate binding 2. Key physiological substrates include truncated selenoproteins (SELENOK, SELENOS) resulting from failed UGA/Sec decoding and proteolytically cleaved proteins like the N-terminal fragment of USP1 2. The protein demonstrates distinct subcellular localization patterns, being predominantly nuclear, unlike its paralog KLHDC1 3. KLHDC2 has emerged as a promising therapeutic target, with engineered degraders showing selective degradation of proteins like CDK6, demonstrating potent anti-leukemic activity 45. This positions KLHDC2 as both a critical cellular quality control mechanism and a novel platform for targeted protein degradation therapeutics 6.