Induction of pyroptosis is proposed as a promising strategy for the treatment of hematological malignancies, but little is known. In the present study, we find clioquinol (CLQ), an anti-parasitic drug, induces striking myeloma and leukemia cell pyroptosis on a drug screen. RNA sequencing reveals that the interferon-inducible genes IFIT1 and IFIT3 are markedly upregulated and are essential for CLQ-induced GSDME activation and cell pyroptosis. Specifically, IFIT1 and IFIT3 form a complex with BAX and N-GSDME therefore directing N-GSDME translocalization to mitochondria and increasing mitochondrial membrane permeabilization and triggering pyroptosis. Furthermore, venetoclax, an activator of BAX and an inhibitor of Bcl-2, displays strikingly synergistic effects with CLQ against leukemia and myeloma via pyroptosis. This study thus reveals a novel mechanism for mitochondrial GSDME in pyroptosis and it also illustrates that induction of IFIT1/T3 and inhibition of Bcl-2 orchestrate the treatment of leukemia and myeloma via pyroptosis.

中文翻译：

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IFIT1/IFIT3 的诱导和 Bcl-2 的抑制通过细胞焦亡协调治疗骨髓瘤和白血病

诱导焦亡被认为是治疗血液恶性肿瘤的一种有前途的策略，但人们知之甚少。在本研究中，我们发现氯碘羟喹（CLQ）是一种抗寄生虫药物，在药物筛选中可诱导显着的骨髓瘤和白血病细胞焦亡。 RNA 测序表明，干扰素诱导基因 IFIT1 和 IFIT3 显着上调，并且对于 CLQ 诱导的 GSDME 激活和细胞焦亡至关重要。具体来说，IFIT1 和 IFIT3 与 BAX 和 N-GSDME 形成复合物，因此引导 N-GSDME 转运至线粒体并增加线粒体膜通透性并引发细胞焦亡。此外，venetoclax（BAX 激活剂和 Bcl-2 抑制剂）与 CLQ 通过细胞焦亡显示出惊人的协同作用，对抗白血病和骨髓瘤。因此，这项研究揭示了线粒体 GSDME 在焦亡中的新机制，并且还说明了 IFIT1/T3 的诱导和 Bcl-2 的抑制协调通过焦亡来治疗白血病和骨髓瘤。