Pyroptosis-oriented drug discovery identifies diacerein as a promising therapeutic candidate for glioma

Pyroptosis, a highly inflammatory form of programmed cell death, has recently emerged as a promising therapeutic strategy for glioma because it can both suppress tumor growth and modulate the tumor immune microenvironment. However, the systematic identification of clinically relevant pyroptosis-inducing agents for glioma remains limited. We constructed a dedicated pyroptosis-related compound library by integrating commercially available inducers with candidates identified through comprehensive literature mining of PubMed and Web of Science. To enhance translational feasibility, compounds were sequentially filtered using Lipinski’s rule of five, blood–brain barrier (BBB) permeability prediction, central nervous system multiparameter optimization (CNS-MPO) scoring, and stringent descriptor-based criteria. Further pharmacological and literature-based curation was performed to prioritize candidate molecules. The antitumor effects and underlying mechanisms were subsequently evaluated through in vitro and in vivo experiments. Through this pipeline, Diacerein was identified as a promising candidate. Functional assays demonstrated that Diacerein significantly inhibited glioma cell proliferation and tumor growth. Mechanistically, Diacerein activated caspase-3-associated apoptosis and induced GSDME cleavage, resulting in pyroptosis-like cell death. Importantly, GSDME knockdown partially attenuated Diacerein-induced cytotoxicity and restored glioma cell viability, supporting the functional involvement of GSDME in this process. These effects were accompanied by changes in inflammation-related signaling, including reduced IL-1β / NF-κB / p-STAT3 activity, suggesting a potential association with macrophage-related immune alterations in vivo. Our findings identify Diacerein as a clinically used anti-osteoarthritic drug with previously unrecognized anti-glioma activity involving caspase-3 activation and GSDME-associated pyroptotic signaling. This study highlights the potential of drug repurposing strategies to uncover novel therapeutic mechanisms and provides a new framework for precision treatment of glioma.