ABSTRACT E3 ubiquitin ligases are pivotal regulators within the ubiquitin–proteasome system, conferring specificity to protein ubiquitination and subsequent degradation, thereby maintaining cellular homeostasis. Their structural diversity allows for the precise control of vital processes, including the cell cycle, immune responses, and signal transduction, across various tissues. Despite their profound influence on physiology, a systematic understanding of how specific E3 ligases contribute to distinct disease pathogenesis and their translational potential remains incomplete. This review systematically delineates the classification and catalytic mechanisms of major E3 ligase families, including RING, HECT, and RBR types, and elaborates their pathological roles in driving carcinogenesis, cardiovascular remodeling, autoimmune dysregulation, metabolic syndrome, and neurodegenerative aggregation. We further synthesize recent advances in therapeutic modalities, from small‐molecule inhibitors targeting ligases like MDM2 to novel strategies in targeted protein degradation, notably proteolysis‐targeting chimeras (PROTACs) that hijack E3 machinery. By integrating mechanistic insights with emerging therapeutic landscapes, this work underscores the central role of E3 ligases in human diseases and provides a strategic framework for developing next‐generation, mechanism‐based therapeutics.
Wang et al. (2025) studied this question.