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<p>CARD8 (caspase activation and recruitment domain-containing 8) senses intracellular danger signals, leading to inflammasome formation and pyroptosis. Recently studies have shown that CARD8 was highly expressed in hematopoietic cells, however, the mechanism by which the released C- terminal domain of CARD8 (CARD8-CT) oligomerizes and nucleates, and its role in acute myeloid leukemia (AML) treatment has not been fully understood. Here, we identified a long noncoding RNA IL10RB-AS1 as a novel regulator that can enhance the CARD8-CT oligomer assembly and promote pro-caspase-1-dependent pyroptosis in AML cells. Mechanically, IL10RB-AS1 recruits DEAD-box helicase 3, X-linked (DDX3X) to CARD8 and enhances the DDX3X-CARD8 interaction to promote CARD8-CT nucleation. This process activates the CARD8 inflammasome and triggers an ASC-independent pyroptosis response to perturbations in cellular homeostasis. We found that the C-terminal domain of DDX3X is essential for its interaction with both IL10RB-AS1 and CARD8-CT, facilitating inflammasome activation during AML cell pyroptosis. Importantly, IL10RB-AS1 is highly expressed across AML and correlates with poor outcomes. This elevated expression of IL10RB-AS1 promotes DPP8/9 inhibitor induced pro-caspase-1-dependent pyroptosis in vivo, suggesting that high IL10RB-AS1 levels may predict cellular sensitivity to these inhibitors. Our findings not only reveal a novel mechanism by which a lncRNA orchestrates CARD8-CT nucleation but also highlight new therapeutic opportunities for DPP8/9 inhibitors in hematopoietic malignancies with high IL10RB-AS1 expression.</p>

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IL10RB-AS1 promotes pro-caspase-1-dependent pyroptosis via regulating the oligomerization and nucleation of CARD8 C-terminal domain to suppress acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Qi Pan,
  • Bo He,
  • Li-Bin Huang,
  • Qian-Qian Yang,
  • Cheng-Lin Zhou,
  • Yan An,
  • Xin-Yi Feng,
  • Jian-Ping Lian,
  • Shun-Xin Zhu,
  • Ke-Jia Pu,
  • Heng-Jing Huang,
  • Chen Fang,
  • Yi-Xuan Ma,
  • Chang-Hao Liang,
  • Zi-Yuan Wang,
  • Dan Wang,
  • Wei Huang,
  • Yun-Meng Sun,
  • Yue-Qin Chen,
  • Hua Zhang,
  • Wen-Tao Wang

摘要

CARD8 (caspase activation and recruitment domain-containing 8) senses intracellular danger signals, leading to inflammasome formation and pyroptosis. Recently studies have shown that CARD8 was highly expressed in hematopoietic cells, however, the mechanism by which the released C- terminal domain of CARD8 (CARD8-CT) oligomerizes and nucleates, and its role in acute myeloid leukemia (AML) treatment has not been fully understood. Here, we identified a long noncoding RNA IL10RB-AS1 as a novel regulator that can enhance the CARD8-CT oligomer assembly and promote pro-caspase-1-dependent pyroptosis in AML cells. Mechanically, IL10RB-AS1 recruits DEAD-box helicase 3, X-linked (DDX3X) to CARD8 and enhances the DDX3X-CARD8 interaction to promote CARD8-CT nucleation. This process activates the CARD8 inflammasome and triggers an ASC-independent pyroptosis response to perturbations in cellular homeostasis. We found that the C-terminal domain of DDX3X is essential for its interaction with both IL10RB-AS1 and CARD8-CT, facilitating inflammasome activation during AML cell pyroptosis. Importantly, IL10RB-AS1 is highly expressed across AML and correlates with poor outcomes. This elevated expression of IL10RB-AS1 promotes DPP8/9 inhibitor induced pro-caspase-1-dependent pyroptosis in vivo, suggesting that high IL10RB-AS1 levels may predict cellular sensitivity to these inhibitors. Our findings not only reveal a novel mechanism by which a lncRNA orchestrates CARD8-CT nucleation but also highlight new therapeutic opportunities for DPP8/9 inhibitors in hematopoietic malignancies with high IL10RB-AS1 expression.