From molecular logic to therapeutic modulation: advances in Ub/UBL signalling

Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are central regulators of cell signalling, with roles spanning proteasomal degradation, immune defence, DNA repair, autophagy, and the stress response. Their conserved β-grasp fold provides a remarkably versatile protein architecture that can be redeployed across diverse signalling pathways and modulated in disease contexts. Conjugation and removal through dedicated E1–E2–E3 and protease systems generate a rich regulatory code, further diversified by chain topology, hybrid architectures, and emerging non-canonical modifications. This special issue highlights recent advances in Ub and UBL biology, from specialised UBL pathways to host–pathogen interactions and non-protein conjugation events, as well as translational applications such as targeted protein degradation. Together, these reviews showcase the breadth, adaptability, and therapeutic potential of these small but powerful modifiers.