Targeting the proteasome in cancer therapy: development and future opportunities in natural products

Background: The ubiquitin-proteasome pathway is a critical therapeutic target in malignancies, particularly multiple myeloma. The development of proteasome inhibitors (PIs) has marked a milestone in multiple myeloma therapy and now constitutes the backbone of frontline treatment regimens. However, primary and acquired resistance remain a major challenge, underscoring the need to identify new PIs as well as agents that can resensitize resistant cells. Method: This review provides an overview of the current clinical applications of PIs and offers a comprehensive summary of natural products that either directly target the proteasome or enhance cellular sensitivity to PIs. Relevant clinical trials and literature published up to 2025 were retrieved from PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov, focusing on the biological and pharmacological activities, structure-activity relationships, and clinical outcomes. Results: In this review, we summarize the current clinical applications of PIs and specifically highlight the discovery of natural products that directly target the proteasome or enhance cellular sensitivity to PIs. We also discuss the clinical progress of marizomib, the only natural product-derived PI, that has advanced to clinical trials. Despite existing challenges, natural product-derived PIs hold significant potential for the development of next-generation therapies that can overcome resistance and improve clinical outcomes. Conclusion: The development of novel natural product-derived PIs and rational combination strategies offers promising opportunities for overcoming resistance in cancer therapy. Although challenges remain, the remarkable structural diversity of natural products provides a rich reservoir for drug discovery, underscoring the importance of continued exploration and innovation in this field.