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E3 ubiquitin ligases and their therapeutic potential in disease Management

Madhukar, Geet, Haque, Md Azizul, Khan, Shawez, Kim, Jong-Joo, Danishuddin·2025·Biochemical Pharmacology
DOI 10.1016/j.bcp.2025.116875
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Abstract

Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribut…

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Metadata

Authors
Madhukar, G., Haque, M. A., Khan, S., Kim, J.-J., & Danishuddin
Venue
Biochemical Pharmacology
Publisher
Elsevier BV
Published
2025-06
Volume
236
Pages
116875
ISSN
0006-2952
DOI
10.1016/j.bcp.2025.116875
Cited by
26
References
13
Language
en
Licence

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