Despite the efficacy of bortezomib (BTZ)-based chemotherapy in treating multiple myeloma (MM) patients, chemoresistance occurs frequently over time, particularly in individuals exhibiting an initial positive response to BTZ therapy. In this study, we established BTZ-resistant MM cells and identified that suppressed expression of the hepatoma-derived growth factor (HDGF)-related protein-2 (HRP2) was a key determinant of chemoresistance in MM cells. Manipulating HRP2 expression remodeled the chemosensitivity of MM cells in vitro and in vivo. Clinically, lower expression of HRP2 predicted a shorter survival rate in MM patients receiving BTZ-based regimens. Mechanistically, HRP2 depletion resulted in elevated acetylation modifications of histone 3 at lysine 27 (H3K27Ac), and enhanced chromatin accessibility as well as transcriptional elongation of mitochondrial calcium uptake 1(MICU1) gene, thus promoting the expression of MICU1 gene and alleviating calcium (Ca