Multiple myeloma (MM) is a plasma cell malignancy highly dependent on the protein homeostasis network. MM cells, due to their continuous synthesis and secretion of large amounts of immunoglobulins, have a high dependence on protein folding, transport, and degradation processes; thus, protein homeostasis imbalance not only participates in the occurrence and development of MM but is also closely related to the response to proteasome inhibitor therapy and the formation of drug resistance. USP14 is a proteasome-associated deubiquitinase located on the 26S proteasome, which can participate in the maintenance of intracellular protein homeostasis by regulating the deubiquitination of substrate proteins, the removal of ubiquitin chains, and proteasome function. Recent studies have shown that USP14 plays an important role in the regulation of tumor-related protein homeostasis; in MM, the latest research further suggests that USP14 can participate in tumor progression and ferroptosis resistance by mediating the deubiquitination of SLC7A11. This article reviews the research progress of USP14-mediated protein homeostasis regulation in the occurrence, development, and drug resistance of MM based on the structural and functional characteristics of USP14, and summarizes the potential therapeutic value of targeting USP14, with the aim of providing a reference for related mechanism research and the exploration of targeted intervention strategies.

Yuxiu Yang, Chunge Song, Yiyang Wang, Mengjiao Wu, Rongrong Lv. Research Progress on USP14-Mediated Protein Homeostasis Regulation in the Tumorigenesis, Progression and Drug Resistance of Multiple Myeloma. Frontiers in Medical Science Research (2026), Vol. 8, Issue 3: 56-62. https://doi.org/10.25236/FMSR.2026.080308.

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