Advances in controllable targeted protein degradation: emerging strategies and mechanisms

Controllable targeted protein degradation (controllable TPD) technologies, exemplified by proteolysis-targeting chimeras (PROTACs), have emerged as transformative tools in drug discovery and molecular biology research. With the endogenous cellular degradation machinery, controllable TPD platforms allow for the precise targeting and regulated elimination of specific proteins within cells. Recent advances have expanded the spectrum of controllable degradation strategies, including photosensitive degrons, opto-PROTACs, auxin-inducible degron (AID) systems, small molecule-assisted shut-off (SMASh) techniques, and engineered E3 ubiquitin ligases such as ΔTRIM21 with enhanced targeted protein degradation efficiency (ΔTRIM-TPD). These emerging methodologies provide unprecedented control over protein stability, facilitating targeted therapeutic interventions for diseases such as cancer and infectious diseases, and significantly advancing fundamental biological research. This review systematically summarizes recent breakthroughs in controllable TPD strategies, elucidates their distinct molecular mechanisms, and highlights their promising therapeutic applications. The rapidly evolving field of controllable TPD represents a powerful and adaptable technological frontier, opening new avenues in precision medicine and providing versatile tools for the future of biomedical research.