Multiple myeloma (MM) is a malignant hematological disease caused by the proliferation of abnormal plasma cells in the bone marrow and is still incurable. Relapse and drug resistance are common in MM. New therapeutic targets are urgently needed for MM treatment. Human antigen R (HuR) has been reported to play an important role in the malignant biological behavior of a variety of tumors, but its role in MM remains unclear. In this study, we found that HuR was highly expressed in MM patients and associated with a poor prognosis by analyzing public datasets. We found that targeting HuR with short hairpin RNA (shRNA) or its inhibitor CMLD-2 had significant anti-MM effects both in vitro and in vivo. The overexpression of HuR promotes MM cell proliferation in vitro and in vivo. Moreover, we demonstrated that bortezomib drug sensitivity increased and decreased with the knockdown and overexpression of HuR, respectively. This result provides a rationale for our subsequent combination of CMLD-2 with bortezomib in the treatment of MM. To further explore the mechanism of HuR in MM, we performed RNA sequencing and identified its downstream molecule, E2F7. HuR upregulated E2F7 expression by increasing the stability of its mRNA in MM cells. Higher levels of E2F7 were associated with a poorer prognosis. E2F7 knockdown had anti-MM effects in vitro and in vivo. E2F7 overexpression partially rescued the cell proliferation inhibition and apoptosis caused by targeting HuR in MM cells. We subsequently demonstrated that CMLD-2 synergized with the anti-MM effect of bortezomib both in vitro and in vivo. In conclusion, targeting the HuR/E2F7 axis synergizes with bortezomib against MM. Therefore, the HuR/E2F7 axis may serve as a promising therapeutic target for MM.© 2025. The Author(s).