Evidence has shown that in mouse myeloid cells, small molecular inhibitors of the serine dipeptidase Dpp8/9 can activate the caspase-1 signaling pathway via the inflammasome sensor Nlrp1b, which leads to the cleavage and activation of GSDMD and the formation of a pore in the plasma membrane to mediate cell death and inhibit the progression of acute myeloid leukemia (AML) [
19]. Similarly, CARD8 has been identified as a novel inflammasome sensor that can mediate the Dpp8/9 inhibitor-dependent caspase-1 signaling pathway to induce cell death of human myeloid cells. The form of death induced by Dpp8/9 inhibitors in these two types of cells is called pyroptosis. DPP8/9 inhibitors can induce pyroptosis in most human AML cell lines and primary AML samples but not in many other lineages [
18]. Interestingly, gene expression analysis showed that upregulated expression of BAY-299 could promote the expression of pyroptosis-related genes, and activation of the caspase-1 or caspase-4, 5, and 11 pathway could induce GSDMD-induced pyroptosis [
20]. Alternatively, caspase-3 can be activated to cleave GSDME to induce pyroptosis independent of caspase-1 and GSDMD [
3]. In addition to the factors in these two important pathways, GSDMA, GSDMB, and GSDMC also contain a pore-forming domain that can induce pyroptosis. Cytotoxic lymphocyte-derived granzyme A is able to cleave GSDMB and induce tumor cell pyroptosis [
21]. GSDMB promotes cell death by enhancing the activity of caspase-4 [
22]. However, the exact mechanisms by which GSDMA and GSDMC can be activated and their role in pyroptosis are still unclear. After BAY-299 treatment, the expression of caspase-1, caspase-4, GSDMB, GSDMC, GSDMD, and GSDME in AML cells increases, suggesting that BAY-299 treatment induces apoptosis and triggers pyroptosis. In addition, BAY-299 treatment makes AML cells more sensitive to induced pyroptosis. It is worth noting that the DPP8/9 inhibitors mentioned above are promising for the treatment of AML. Therefore, compared with single treatment, combination with BAY-299 treatment to induce cell death may be a more effective treatment strategy [
20]. Through the analysis of candidate genes of primary T cells, we found that the response depends on CARD8-caspase-1-GSDMD signaling. Interestingly, the CARD8-induced pyroptosis pathway can only be activated in a resting state, not under T cell activation. These findings support a correlation between inflammasome signaling pathways and T cells, core components of the adaptive immune system [
23]. Curcumin has antileukemia activity. Curcumin can induce the expression of AIM2, IFI16, and the NLRC4 inflammasome in U937 leukemia cells by upregulating the expression of the ISG3 transcription factor complex and then activating caspase-1, promoting the cleavage of GSDMD to induce cell death. In addition, overexpression of exogenous GSDMD induced by lentivirus transfection in K562 cells can enhance the anticancer activity of curcumin, while silencing its expression enhances the resistance of U937 cells to curcumin, suggesting that induction of cell death is a mechanism by which curcumin induces antileukemic effects [
24]. Some studies have shown that ardisianone can induce the cleavage of caspase-1, caspase-5, and GSDMD and increase the expression of HMGB1 protein to some extent, indicating a role of ardisianone in inducing pyroptosis in HL60 cells [
25]. Many studies have shown that caspase-8 activity and necrotic cell death activated by GSDMD occur via the same signaling pathway [
5•,
26]. There is also evidence suggesting that activated caspase-8 can cleave GSDMD, emphasizing the role of caspase-8 in promoting pyroptosis [
5•]. Our data show synchronization of the activation of caspase-1, caspase-5, and caspase-8 and the cleavage of GSDMD, suggesting that the caspase activation pathway plays a key role in ardisianone-induced pyroptosis [
25]. Application of recombinant Tp92 protein induced the death of the human monocyte cell line THP-1, which was derived from a patient with acute monocytic leukemia, by recognizing cell surface CD14 or TLR2. Stimulation of THP-1 cells with Tp92 protein may induce atypical pyroptosis of THP-1 cells by promoting the caspase-1 pathway [
27]. Some studies have shown that necrosulfonamide (NSA), an inhibitor of pyroptosis, can selectively induce highly toxic DNA double-strand breaks and kill AML cells. Reactive oxygen species (ROS) are the key effector substances that mediate NSA toxicity [
28]. NSA specifically targets the N-terminal coiled-coil domain of the key programmed necrotic effector mixed lineage kinase domain-like protein (MLKL) to prevent programmed necroptosis and directly disrupt the integrity of the membrane, resulting in necrosis [
29,
30]. The active site of NSA is cysteine 86 in human MLKL, but this residue is absent in mouse MLKL. Therefore, NSA specifically functions in humans but does not affect programmed cell death in mice [
30]. However, in human and mouse cells, NSA directly binds to the pyroptotic pore-forming protein GSDMD, inhibiting GSDMD oligomerization and pyroptotic cell death [
31].