Biochemists reported that protein carboxymethyltransferase 1 (PCMT1) generates a C‑terminal degron on substrates of cereblon (CRBN), the E3 ligase adapter central to the activity of thalidomide‑class drugs. The study elucidates a previously unrecognized modification pathway that influences CRBN substrate recognition and turnover. The finding has implications for targeted protein degradation strategies and for understanding off‑target effects of cereblon‑binding therapeutics such as lenalidomide. Drug developers working on molecular glues, cereblon ligands or degrader platforms may reassess substrate engagement models and consider PCMT1’s role during lead optimization.