KLHDC10 (kelch domain containing 10) functions as a substrate-recognition component of the CRL2 (Cul2-RING) E3 ubiquitin ligase complex, which targets proteins for ubiquitin-dependent degradation via the DesCEND pathway 12. The complex specifically recognizes C-degrons—short peptide motifs at protein C-termini, particularly proline-glycine or alanine tails (CAT tails)—leading to substrate ubiquitination 34. KLHDC10 possesses a U-shaped degron-binding pocket with conformational malleability that enables recognition of varying C-terminal sequences, distinguishing it from related KLHDC family members 4. A critical function involves ribosome-associated quality control (RQC), where CRL2(KLHDC10) acts downstream of NEMF to recognize and degrade incompletely synthesized nascent chains bearing alanine tails from stalled ribosomes 25. Beyond RQC, KLHDC10 participates in oxidative stress responses by inhibiting protein phosphatase 5 (PP5) activity on MAP3K5, thereby promoting sustained ASK1 activation and stress-induced cell death through MAPK pathways 6. Disease relevance is indicated by association with colorectal cancer risk through DNA methylation regulation 7. These functions position KLHDC10 as a key regulator of protein quality control and cellular stress responses.