GSDME (gasdermin E) is a pore-forming protein that executes pyroptosis, a form of inflammatory programmed cell death 1. GSDME is activated through caspase-3 cleavage of its linker domain, releasing an N-terminal fragment that perforates cell membranes 2. This activation can be triggered by chemotherapy drugs, TNF, and granzyme B from cytotoxic lymphocytes 23. GSDME functions as a tumor suppressor by converting apoptotic signals to pyroptosis, which enhances anti-tumor immunity through increased phagocytosis by macrophages and activation of CD8+ T cells and natural killer cells 3. However, dysregulated GSDME-mediated pyroptosis contributes to pathological inflammation in atherosclerosis, where GSDME is highly expressed in macrophages and regulated by STAT3 4. In the nervous system, GSDME mediates mitochondrial damage and axon loss in neurodegeneration, with GSDME knockout extending survival in ALS models 5. Recently, GSDME-mediated pyroptosis was identified as a driver of immune checkpoint inhibitor-induced myocarditis through cGAS-STING-interferon activation 6. GSDME phosphorylation by AMPK at Thr6 negatively regulates pyroptosis and can be enhanced by mannose metabolism, offering therapeutic potential to reduce chemotherapy toxicity 7. GSDME mutations associated with autosomal dominant deafness disrupt its pore-forming function 2.