Targeting the ubiquitin-proteasome pathway in systemic lupus erythematosus

The ubiquitin-proteasome system (UPS) is the major non-lysosomal mechanism for selective degradation of intracellular proteins that is essential for the regulation of cellular functions and survival. Modulation of the proteasomes and cereblon E3 ligase promotes degradation of polyubiquitin-tagged transcription factors and oncoproteins, leading to depletion of long-lived plasma cells, diminished autoantibody and interferon-α production, reduced T-cell polarization to the proinflammatory phenotypes and increased regulatory T-cell activity that are relevant to the therapy of systemic lupus erythematosus (SLE).

Selective immunoproteasome inhibitors and newer generation cereblon modulators have improved safety profiles compared to conventional compounds. This article summarizes the literature regarding the modulation of the UPS in murine and human SLE.

Bortezomib and the selective immunoproteasome inhibitors, ONX-0914 and zetomipzomib, ameliorate renal disease in murine lupus models. While clinically effective in refractory SLE, bortezomib is limited by its toxicities. Zetomipzomib shows promising data in phase Ib/II studies of SLE and lupus nephritis. Thalidomide and lenalidomide are effective in refractory cutaneous lupus but again limited by their off-target effects. A phase II RCT of iberdomide shows favorable results in SLE, especially chronic and subacute cutaneous lesions. These molecules should be further explored in larger clinical trials of renal and cutaneous SLE.