Gasdermin E: Bridging Pyroptosis, Immunity, and Disease Pathogenesis Toward Precision Intervention

Gasdermin E (GSDME), a pivotal executor of pyroptosis, has emerged as a central regulator of immune responses across a spectrum of diseases. Initially identified as a tumor suppressor and a deafness-associated gene (DFNA5), GSDME is now recognized for its complex, context-dependent roles in health and pathology. Its activation, primarily via caspase-3 cleavage, converts apoptotic signals into a lytic, pro-inflammatory form of cell death, releasing damage-associated molecular patterns and cytokines that profoundly shape the immune microenvironment. This review synthesizes the current research landscape of GSDME, detailing its structural characteristics and canonical activation mechanisms, alongside recent discoveries of non-canonical, cleavage-independent pathways. We systematically dissect its dualistic functions in major disease categories-cancer, inflammatory/autoimmune disorders, neurodegenerative conditions, and organ injuries-highlighting the key cell-type-specific signaling pathways and their resultant immunomodulatory outcomes. Furthermore, we evaluate the burgeoning clinical potential of GSDME as a diagnostic/prognostic biomarker and a therapeutic target. We critically analyze the functional characteristics of emerging pharmacological strategies designed to either activate or inhibit the GSDME pathway, including small molecules, epigenetic modulators, and advanced nanoplatforms. Finally, we outline future research directions and propose a framework for the clinical translation of GSDME-targeted therapies, emphasizing the need for precision medicine approaches to harness its immunostimulatory potential in oncology while restraining its pathological role in inflammatory diseases.