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There have been persistent concerns about the safety risks associated with DDT residues in the environment. Studies have shown that exposure to DDT or its metabolites can cause various liver diseases. However, the mechanisms of liver toxicity haven't been well studied. In our current investigation, we observed that DDT triggers pyroptosis in human liver cells (HL-7702), representing a novel form of programmed cell death. Our results delineated DDT (0–100 μM) induced pyroptosis in HL-7702 cells, which was confirmed through morphological changes, lactate dehydrogenase (LDH) release, gasdermin E (GSDME) cleavage and Annexin-V/PI staining. Knockdown of GSDME reduced cell death and transferred the mode of cell death from pyroptosis to apoptosis. Notably, DDT exposure markedly increased reactive oxygen species (ROS) production, concurrent with c-Jun N-terminal kinase (JNK) phosphorylation. Intervention with a ROS inhibitor or JNK inhibitor SP600125 restored cell viability and hindered GSDME-mediated pyroptosis. Our results firstly demonstrate that DDT suppresses HL-7702 cells growth by inducing pyroptosis mainly through the ROS/JNK/GSDME pathway. These findings not only contribute to an in-depth understanding of DDT toxicity but also open avenues for gaining valuable insights into potential mitigation strategies and therapeutic interventions. [Display omitted] • The study revealed the health risks linked to the impact of the pesticide DDT on human liver cells. • Our study has identified, for the first time, that DDT induced pyroptosis in HL-7702 cells. • The underlying mechanism behind DDT-induced pyroptosis was associated with ROS/JNK/GSDME pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel GNA derivatives were synthesized and screened for their antitumor activities. • Introduction of sulfoximines increased the antitumor activity of GNA derivatives. • 12 k with CF 3 group displayed the most pronounced anti-cancer efficacy. • 12 k triggered pyroptosis in cancer cells via the caspase-3/GSDME pathway. Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi , exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12 k , which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12 k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12 k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery. [ABSTRACT FROM AUTHOR]