Erianin induces GSDMD-dependent pyroptosis and synergistically enhances doxorubicin efficacy via the PI3K/AKT signaling pathway in diffuse large B-cell lymphoma

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is characterized by high aggressiveness and rapid growth. Erianin, a natural compound derived from the Chinese herb Dendrobium, has been shown to exhibit anticancer effects in certain types of cancer; however, its role and mechanism of action in DLBCL have not yet been reported. Therefore, this study aimed to investigate the potential of erianin as a therapeutic drug for DLBCL. METHODS: The cell counting kit-8 assay, lactate dehydrogenase release assay, flow cytometry, and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to assess the inhibitory effect of erianin on DLBCL cells. RNA sequencing, western blotting, immunofluorescence, and flow cytometry were used to investigate the molecular mechanisms of the effect of erianin on DLBCL cells. Erianin was labeled with biotin or rhodamine, and its target proteins were identified using pull-down assays combined with proteomics, cellular thermal shift assays, and molecular docking. CompuSyn software was used to analyze the combination index of erianin and doxorubicin (DOX) for evaluating their synergistic anti-DLBCL effects. Results from the in vitro experiments were subsequently validated using in vivo experiments. RESULTS: Erianin inhibited the proliferation of DLBCL cells, promoted G2/M phase arrest, and induced cell death. Mechanistically, erianin induced inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in DLBCL cells, which led to increased reactive oxygen species (ROS) formation, inflammasome activation, and caspase-1/GSDMD-dependent pyroptosis. Erianin was found to bind to the S100A9 protein, suggesting a potential mechanism through which erianin activates downstream signaling pathways. Moreover, erianin synergistically enhanced the effects of DOX on DLBCL. CONCLUSIONS: Our study demonstrates that erianin binds to S100A9 and suppresses the PI3K/AKT signaling pathway in DLBCL cells, thereby elevating ROS levels, activating the inflammasome, and triggering caspase-1/GSDMD-dependent pyroptosis. Moreover, erianin increased the sensitivity of DLBCL cells to DOX both in vitro and in vivo. The effects of erianin on DLBCL imply its potential in the development of promising new drugs against this disease.