Research Progress on E3 Ubiquitin Ligase in Targeted Protein Degradation

Proteolysis targeting chimera（PROTAC） technology, a revolutionary approach in the field of targeted protein degradation,opens a new avenue for the development of drugs targeting previously “undruggable” proteins by leveraging the cell’s endogenous ubiquitin-proteasome system（UPS）. The core of this technology lies in the design of its bifunctional molecules: one end binds to the protein of interest（POI）, while the other recruits an E3 ubiquitin ligase, thereby inducing ubiquitination of the POI and facilitating its degradation by proteasome. The E3 ubiquitin ligase, as one of the key components of PROTAC technology, has a decisive impact on the design and degradation efficiency of PROTAC molecules due to its selection, characteristics, and functions. This article reviews recent advances in research on E3 ubiquitin ligase within the PROTAC field, explores the discovery of novel E3 ubiquitin ligases, and discusses future directions, aiming to provide valuable insights for further optimization and application of PROTAC technology.