多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤，其中泛素-蛋白酶体途径的功能异常与病理发生相关。泛素髓鞘贮存蛋白（VCP）/p97是AAA+ ATP酶家族的成员，具有调节蛋白质质量控制包括泛素-蛋白酶体系统及分子伴侣的多种功能。VCP参与了多种肿瘤的发生和发展，而在MM中的作用仍不明确。VCP抑制剂逐渐显示出在癌症治疗中的巨大潜力。本研究旨在确定VCP是否是MM的治疗靶点，并证实一种新型VCP抑制剂（VCP20）对MM的作用。我们发现VCP在MM患者中升高，并与临床TT2队列中的较短生存相关。使用siRNA沉默VCP通过NF-κB信号通路结果降低MM细胞增殖。VCP20明显抑制MM细胞增殖和破骨细胞分化。此外，包含MM细胞来源的VCP的外泌体部分减轻了VCP20对细胞增殖和破骨细胞分化的抑制作用。机制研究显示，VCP20通过抑制IκBα的泛素化降解失活了NF-κB信号通路。此外，VCP20抑制了MM细胞增殖，在MM模型小鼠中延长了生存时间，并改善了骨破坏。总的来说，我们的发现表明VCP是MM进展的一个新的靶点。使用VCP20靶向VCP通过抑制NF-κB信号通路抑制了MM的恶性进展。

Multiple myeloma (MM) is the second most common hematological malignancy, in which the dysfunction of the ubiquitin-proteasome pathway is associated with the pathogenesis. The valosin containing protein (VCP)/p97, a member of the AAA+ ATPase family, possesses multiple functions to regulate the protein quality control including ubiquitin-proteasome system and molecular chaperone. VCP is involved in the occurrence and development of various tumors while still elusive in MM. VCP inhibitors have gradually shown great potential for cancer treatment. This study aims to identify if VCP is a therapeutic target in MM and confirm the effect of a novel inhibitor of VCP (VCP20) on MM. We found that VCP was elevated in MM patients and correlated with shorter survival in clinical TT2 cohort. Silencing VCP using siRNA resulted in decreased MM cell proliferation via NF-κB signaling pathway. VCP20 evidently inhibited MM cell proliferation and osteoclast differentiation. Moreover, exosomes containing VCP derived from MM cells partially alleviated the inhibitory effect of VCP20 on cell proliferation and osteoclast differentiation. Mechanism study revealed that VCP20 inactivated the NF-κB signaling pathway by inhibiting ubiquitination degradation of IκBα. Furthermore, VCP20 suppressed MM cell proliferation, prolonged the survival of MM model mice and improved bone destruction in vivo. Collectively, our findings suggest that VCP is a novel target in MM progression. Targeting VCP with VCP20 suppresses malignancy progression of MM via inhibition of NF-κB signaling pathway.