BACKGROUND: Multiple myeloma (MM) is a malignant disorder originating from plasma cells. Bortezomib (BTZ) resistance has become a huge obstacle to MM treatment. Herein, we elucidated the action of Kruppel-like factor 2 (KLF2), a crucial transcription factor (TF), on BTZ resistance of MM. METHODS: Two BTZ-resistant cell lines (MM1.S/BTZ and NCI-H929/BTZ) were generated and used. KLF2 mRNA was quantified by quantitative PCR, and protein expression was analyzed by immunoblotting. MTT cell cytotoxicity assay was used to test BTZ sensitivity. Cell growth was detected by MTT and EdU assays. Flow cytometry was used for apoptosis and cycle distribution analyses. The USP4/KLF2 relationship was examined by Co-IP and protein stability assays. The KLF2/HMGA2 interplay was confirmed by luciferase and ChIP assays. RESULTS: Upregulation of KLF2 was observed in MM serum and BTZ-resistant MM cells. Depletion of KLF2 suppressed cell growth and enhanced apoptosis and BTZ sensitivity in MM1.S/BTZ and NCI-H929/BTZ cells. Moreover, USP4 increased the stability of KLF2 protein by deubiquitination and affected cell growth, apoptosis and BTZ sensitivity via KLF2. KLF2 functioned as a regulator of HMGA2 transcription and modulated cell growth, apoptosis and BTZ sensitivity through HMGA2. Additionally, USP4 modulated HMGA2 expression via KLF2 in the two BTZ-resistant cell lines. CONCLUSION: Our study demonstrates the crucial role of the USP4/KLF2/HMGA2 cascade in regulating cell growth, apoptosis and BTZ sensitivity in BTZ-resistant MM cells, providing novel targets for improving anti-MM efficacy of BTZ.