KLHDC1 (kelch domain containing 1) is a cytoplasmic substrate-recognition component of the Cul5-RING (CRL5) E3 ubiquitin-protein ligase complex 1. It functions within the DesCEND (destruction via C-end degrons) pathway, recognizing C-degrons—motifs of fewer than ten residues at the extreme C-terminus of target proteins—to direct their ubiquitination and proteasomal degradation 1. The CRL5(KLHDC1) complex mediates ubiquitination of truncated selenoproteins, including SELENOS variants arising from failed UGA/Sec codon decoding 1. Structurally, KLHDC1 is a paralog of KLHDC2, sharing ~50% amino acid identity, though they exhibit distinct subcellular localizations and biological activities; unlike the nuclear KLHDC2, KLHDC1 resides in the cytoplasm and does not interact with transcription factor LZIP 2. Both proteins are highly expressed in skeletal muscle 2. KLHDC1's selective recognition of C-degrons provides substrate specificity distinct from other KLHDC family members, making it a potential target for therapeutic protein degradation strategies, including PROTAC-based approaches that can discriminate between KLHDC paralogs 3.