Gasdermin E (GSDME) (GSDME)

Gasdermin E (GSDME), originally identified as DFNA5, is a key executioner of pyroptosis, a highly inflammatory form of programmed cell death (UniProt: O60437). It functions as a molecular switch that converts caspase-3-mediated apoptosis into pyroptosis; upon cleavage by caspase-3, the N-terminal fragment of GSDME translocates to the plasma membrane to form large pores, resulting in cell swelling and the release of proinflammatory cytokines (Wang et al., Nature 2017). In the context of oncology, GSDME is frequently silenced by promoter methylation in various cancers, suggesting a role as a tumor suppressor (Akino et al., BMC Cancer 2007). Restoring GSDME expression or activating it with chemotherapeutic agents like cisplatin or paclitaxel can enhance anti-tumor immunity by turning "cold" tumors "hot" through the release of damage-associated molecular patterns (DAMPs) (Zhang et al., Nature 2020). However, high GSDME expression in normal tissues is also a primary driver of chemotherapy-induced side effects, such as tissue damage and organ toxicity, making it a complex therapeutic target (Shen et al., Cell Research 2021). Its role in hearing loss is also well-documented, as mutations in the GSDME gene are linked to autosomal dominant nonsyndromic hearing loss (Van Laer et al., Nature Genetics 1998).

Other names

DFNA5Deafness autosomal dominant 5ICERE-1Inversely correlated with estrogen receptor expression 1

Caspase-3-mediated cleavage of GSDME releases its N-terminal pore-forming domain, which perforates the cell membrane to induce pyroptotic cell death.