GID4 (glucose-induced degradation deficient complex 4) is a substrate-recognition subunit of the CTLH E3 ubiquitin-protein ligase complex that mediates selective protein degradation via the ubiquitin-proteasome system 1. GID4 functions as a degron receptor that recognizes Pro/N-degrons—degradation signals consisting of an N-terminal proline followed by specific small residues, with highest affinity for Pro-Gly-Leu-Trp 2. Notably, GID4 also recognizes non-proline N-terminal residues including isoleucine and valine in appropriate sequence contexts 34. The complex engages two independent substrate recruitment modules; GID4 functions alongside WDR26, which recruits substrates like HBP1 through distinct mechanisms 5. Endogenous GID4 substrates include nucleolar proteins (DDX21, DDX50), metabolic enzymes (HMGCS1), and ARHGAP11A, a RhoGAP regulating cell migration 67. Clinically, GID4 has emerged as a promising E3 ligase for targeted protein degradation (TPD) strategies, with GID4-based PROTACs demonstrating efficacy in degrading oncogenic kinases (EML4-ALK, EGFR, BRD4) and exhibiting antiproliferative activity in non-small cell lung cancer models 8910. These advances expand the repertoire of exploitable E3 ligases for therapeutic protein degradation applications.