将B细胞淋巴瘤2（Bcl-2）识别为治疗青春期骨髓性白血病（AML）的治疗靶点，已经引起了一种范式转变。由于其细胞毒性和免疫原性效应，焦痂病是一种新型的抗肿瘤治疗机制。文特克拉克斯（venetoclax）与低甲基化剂（HMAs）的联合应用已经显示出持久反应并显著改善AML患者的预后。然而，我们对此联合活性的机制的理解仍在不断发展。我们研究了Bcl-2抑制剂文特克拉克斯是否诱导AML细胞焦亡以及鉴定了焦亡效应蛋白。通过使用Western blotting、免疫沉淀、RNA干扰、CCK8实验和LDH实验，我们探索了焦亡效应的机制。我们调查了焦亡效应蛋白GSDME的表达与AML预后之间的关系。我们研究了GSDME去甲基化与文特克拉克斯治疗的焦亡效应的关系，并在小鼠模型和临床样本中进行了验证。文特克拉克斯诱导的焦亡是通过依赖于caspase-3的GSDME裂解来介导的。在机制上，文特克拉克斯通过激活内源性凋亡途径上调caspase-3和GSDME的裂解。通过公共数据库和患者样本分析，我们发现GSDME在AML中通过启动子甲基化下调，并且低GSDME表达与糟糕预后显著相关。体内外实验表明，GSDME过表达或HMAs介导的GSDME表达修复显著增加了AML中文特克拉克斯诱导的焦亡。GSDME介导的焦亡可能是Bcl-2抑制剂的抗白血病效应的一个新的方面。该发现为潜在的生物标志物和治疗策略提供了新的见解，解释了文特克拉克斯和HMAs在AML中的临床活性。© 2023年。BioMed Central Ltd，Springer Nature的一部分。

The identifying of B-cell lymphoma 2 (Bcl-2) as a therapeutic target has led to a paradigm shift in acute myeloid leukemia (AML) treatment. Pyroptosis is a novel antitumor therapeutic mechanism due to its cytotoxic and immunogenic effects. The combination of venetoclax and hypomethylating agents (HMAs) has been shown to lead to durable responses and significantly improve prognosis in patients with AML. However, our understanding of the mechanisms underlying this combinatorial activity is evolving.We investigated whether the Bcl-2 inhibitor venetoclax induces AML cell pyroptosis and identified pyroptosis effector proteins. Via using western blotting, immunoprecipitation, RNA interference, CCK8 assays, and LDH assays, we explored the mechanism underlying the pyroptotic effect. The relationship between the expression of the pyroptosis effector protein GSDME and AML prognosis was investigated. The effect of GSDME demethylation combined with venetoclax treatment on pyroptosis was investigated and confirmed in mouse models and clinical samples.Venetoclax induces pyroptosis that is mediated by caspase-3-dependent GSDME cleavage. Mechanistically, venetoclax upregulates caspase-3 and GSDME cleavage by activating the intrinsic apoptotic pathway. GSDME is downregulated in AML by promoter methylation, and low GSDME expression is significantly associated with poor prognosis, based on public databases and patient sample analysis. In vivo and in vitro experiments showed that GSDME overexpression or HMAs-mediated restoration of GSDME expression significantly increased venetoclax-induced pyroptosis in AML.GSDME-mediated pyroptosis may be a novel aspect of the antileukemic effect of Bcl-2 inhibitors. This finding offers new insights into potential biomarkers and therapeutic strategies, identifying an important mechanism explaining the clinical activity of venetoclax and HMAs in AML.© 2023. BioMed Central Ltd., part of Springer Nature.