Acevaltrate overcomes myeloma resistance to bortezomib via pyroptosis by promoting BAX translocalization to mitochondria

Bortezomib is a mainstay drug for the treatment of myeloma, a malignancy of plasma cells, but resistance frequently develops. Overcoming bortezomib resistance is urgently needed. In the present study, we found that acevaltrate, an active ingredient from a traditional Chinese medicine, exhibits potent activity in triggering pyroptosis in bortezomib-resistant myeloma cells. Mechanistically, acevaltrate induces myeloma cells pyroptosis in a Caspase-3 and GSDME-dependent manner. When Caspase-3 is inhibited by its specific inhibitor or GSDME is knocked out, myeloma cells fail to undergo pyroptosis triggered by acevaltrate. Moreover, acevaltrate promotes the production of reactive oxygen species and strikingly reduces mitochondrial membrane potential. Consistent with this finding, acevaltrate dissociates BAX from its inhibitor, Bcl-2, thereby promoting BAX translocalization to mitochondria. Furthermore, IFIT3, an IFN-inducible protein, is upregulated by acevaltrate. Interestingly, while IFIT3 fails to directly induce myeloma cells pyroptosis, it markedly enhances acevaltrate-induced pyroptosis. IFIT3 binds to Bcl-2 and prevents it from interacting with BAX. Lastly, acevaltrate effectively triggers pyroptosis in bortezomib-resistant myeloma cells. Pre-treatment with acevaltrate significantly restores the sensitivity of resistant myeloma cells to bortezomib. Therefore, acevaltrate strongly induces myeloma cell pyroptosis and overcomes bortezomib resistance. Given its potent activity against myeloma and its established safety profile, acevaltrate warrants further evaluation in clinical settings for its potential to overcome myeloma resistance to bortezomib.