IFI27 and BAX are Essential for GSDME-Mediated Myeloma Cell Pyroptosis

Induction of pyroptosis is a novel strategy for multiple myeloma (MM) treatment, but the underlying mechanism remains elusive. In the analysis of the transcriptomic profile in pyroptotic MM cells, we find the interferon-alpha inducible protein IFI27 is strikingly upregulated. IFI27 is downregulated in MM cells in association with poor prognosis, but its overexpression displays great potency to trigger pyroptosis in both MM cell lines and newly diagnosed MM cells in a GSDME-dependent manner. Moreover, ectopic IFI27 impairs mitochondrial structure and function. Interestingly, when mitochondria are depleted, IFI27 almost fails to induce MM cell pyroptosis. Mechanistic studies show that IFI27 recruits N-GSDME to mitochondria via BAX, therefore triggering pyroptosis. When IFI27 is knocked down, MM cells hardly undergo pyroptosis even when triggered by N-GSDME, BAX, or chemotherapeutic agents. Although GSDMD induces cell pyroptosis independent of BAX, BAX is required for IFI27- and N-GSDME-induced cell pyroptosis. Lastly, ectopic IFI27 promotes GSDME activation and triggers MM cell pyroptosis in vivo and strikingly prolongs the survival of mice with MM. In summary, the present study finds that IFI27 and BAX are essential for GSDME-mediated cell pyroptosis, and induction of IFI27 may represent a promising strategy for the treatment of MM expressing GSDME.