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Targeting the ubiquitin-proteasome pathway in systemic lupus erythematosus
1Department of Medicine, Tuen Mun Hospital, Hong Kong, SAR, China.
Expert Review of Clinical Immunology
|April 23, 2025
Summary
Targeting the ubiquitin-proteasome system (UPS) with specific inhibitors shows promise for treating systemic lupus erythematosus (SLE). These therapies reduce inflammation and improve disease markers in preclinical and early clinical studies.
Area of Science:
- * Molecular Biology and Immunology
- * Drug Discovery and Development
Background:
- * The ubiquitin-proteasome system (UPS) is crucial for regulating cellular functions through protein degradation.
- * Modulating the UPS, including proteasomes and cereblon E3 ligase, impacts key pathways in systemic lupus erythematosus (SLE).
- * Targeting the UPS can deplete plasma cells, reduce autoantibody production, and modulate T-cell responses relevant to SLE therapy.
Purpose of the Study:
- * To review the literature on modulating the UPS for treating murine and human SLE.
- * To evaluate the efficacy and safety of selective immunoproteasome inhibitors and cereblon modulators in SLE.
Main Methods:
- * Literature review of studies involving UPS modulators in SLE models and patients.
- * Analysis of clinical trial data for drugs targeting proteasomes and cereblon.
Main Results:
- * Bortezomib, ONX-0914, and zetomipzomib demonstrated efficacy in murine lupus nephritis models.
- * Zetomipzomib shows promise in early-phase SLE and lupus nephritis trials.
- * Thalidomide, lenalidomide, and iberdomide show effectiveness in cutaneous lupus, with iberdomide demonstrating favorable results in a Phase II trial.
Conclusions:
- * Selective immunoproteasome inhibitors and novel cereblon modulators offer improved safety profiles.
- * Further clinical trials are warranted to explore the potential of these UPS-targeting agents in renal and cutaneous SLE.
- * UPS modulation represents a promising therapeutic strategy for SLE management.
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