# E3 ubiquitin ligases: structural diversity, dysregulation in disease, and their emerging role in targeted therapeutic strategies

## TL;DR

This review explores E3 ubiquitin ligases, their role in cellular processes, their involvement in diseases like cancer and neurodegeneration, and new therapies targeting them.

## Contribution

The paper provides an integrated overview of E3 ligase families, their roles in disease, and emerging therapeutic strategies like PROTACs and AI-driven approaches.

## Key findings

- E3 ligases are central to proteostasis, DNA repair, and immune regulation.
- Dysregulation of E3 ligases contributes to cancer, neurodegeneration, and immune dysfunction.
- PROTACs and AI-guided design are promising for targeted protein degradation therapies.

## Abstract

The Ubiquitin-Proteasome System (UPS) is a key mechanism of cellular homeostasis. A central part of this mechanism is E3 ubiquitin ligases, which selectively direct proteins to be ubiquitinated for degradation via the UPS. In this review we give an integrated overview of the classification, structural and the functional characteristics of the main families of E3 ligases, i.e., RING, HECT, RBR and RCR E3 ligases, as well as non-canonical ligase families. Furthermore, we describe how these ligases contribute to several important biological processes like proteostasis, DNA-repair, cell-cycle control, immune-regulation and neurodegeneration. Here we present examples of diseases that occur due to abnormal functioning of E3 ligases (e.g., cancers, neurodegenerative diseases and immune dysfunctions). Finally, the review also covers emerging therapeutic strategies based on E3 ligases with an emphasis on proteolysis-targeting chimeras (PROTACs) and the use of E3 ligase-modulatory approaches to improve CAR-T-cell-based immunotherapies. Recent developments in artificial intelligence and machine learning have already transformed E3-ligase research through the possibility of high-throughput ligand screening, structure-function prediction and rational design of degraders. Our review aims to integrate our knowledge of E3 ligases and show how converging biochemistry, immunotherapy and AI-driven research can lead to novel precision strategies for targeted protein degradation.

E3 ubiquitin ligases as central regulatory hubs in physiology, disease, and therapeutic innovation. E3 ligases coordinate cellular homeostasis by regulating cell cycle progression, proteostasis, and DNA repair. Dysregulation of E3-mediated ubiquitin signaling contributes to diverse disease states, including cancer, neurodegeneration, and genetic disorders. Advances in therapeutic exploitation of E3 ligases have enabled targeted protein degradation strategies such as PROTACs, emerging immunotherapeutic approaches including CAR-T cell therapy, and AI-guided design frameworks that accelerate discovery and optimization of E3-based interventions. Created in BioRender. Krishnakumar, P. (2026) https://BioRender.com/d19nlqd.Diagram illustrates the central role of E3 ligase in cellular homeostasis, disease-associated dysregulation such as cancer, neurodegeneration, and genetic diseases, and therapeutic opportunities including PROTACs, CAR T-cell therapy, and AI-guided design, with supporting cell cycle, proteasomal degradation, and DNA repair icons.

E3 ubiquitin ligases as central regulatory hubs in physiology, disease, and therapeutic innovation. E3 ligases coordinate cellular homeostasis by regulating cell cycle progression, proteostasis, and DNA repair. Dysregulation of E3-mediated ubiquitin signaling contributes to diverse disease states, including cancer, neurodegeneration, and genetic disorders. Advances in therapeutic exploitation of E3 ligases have enabled targeted protein degradation strategies such as PROTACs, emerging immunotherapeutic approaches including CAR-T cell therapy, and AI-guided design frameworks that accelerate discovery and optimization of E3-based interventions. Created in BioRender. Krishnakumar, P. (2026) https://BioRender.com/d19nlqd.