ABSTRACT Molecular glue degraders (MGDs) represent an emerging therapy that exploits ubiquitin–proteasome pathways to eliminate otherwise intractable proteins. By stabilizing E3 ligases–target protein interactions, they enable event‐driven degradation, advancing targeting of undruggable proteins. Although progress in mechanisms and applications, a coherent framework across disciplines is still lacking. Here, we provide a unified synthesis of MGD mechanisms, including allosteric activation, interface stabilization, and neo‐substrate engagement, and delineate the functional diversity of representative ligases such as CRBN, VHL, DCAF15 and RNF126. We further organize emerging applications across oncology, immune dysregulation, metabolic imbalance, and neurodegenerative proteinpathies, highlighting how MGDs modulate disease‐relevant pathways. Critical enabling technologies, including chemoproteomics, cryo‐electron microscopy (EM), high‐throughput screening, and artificial intelligence–driven generative modeling are summarized as key engines accelerating glue discovery and ligase expansion. Together, this review provides a conceptual and technological blueprint for the rational development of next‐generation MGDs and aims to unlock transformative therapies for a vast array of diseases rooted in previously undruggable proteins. Furthermore, it offers forward‐looking perspectives on overcoming seminal challenges‐including enhancing target selectivity, broadening the repertoire of exploitable E3 ligases, and achieving precise spatiotemporal control over degradation.
Wen et al. (Tue,) studied this question.