The Role and Mechanism of GSDME-Dependent Pyroptosis in Cochlear Marginal Cells Injury by Cisplatin

TL;DR

This study shows that GSDME-dependent pyroptosis contributes to cisplatin-induced damage in cochlear cells, offering new insights for preventing hearing loss.

Contribution

The study identifies GSDME-mediated pyroptosis as a key mechanism in cisplatin ototoxicity and reveals caspase-3 as an upstream regulator of GSDME.

Findings

Cisplatin exposure activates the caspase-3/GSDME signaling pathway in cochlear marginal cells.

Inhibiting GSDME or caspase-3 reduces cisplatin-induced cellular damage.

Caspase-3 suppression lowers GSDME expression, indicating a regulatory relationship.

Abstract

Background: Elucidating the mechanisms underlying cisplatin-induced ototoxicity is critical for the clinical management of hearing loss. While cisplatin is known to penetrate the inner ear via the blood-labyrinth barrier in the stria vascularis, its precise damaging effects on marginal cells (MCs) and subsequent hearing impairment remain incompletely understood. Pyroptosis, a gasdermin-mediated inflammatory cell death pathway, may play a key role. This study investigated the involvement of gasdermin E (GSDME)-dependent pyroptosis in cisplatin-induced injury to MCs. Methods: An in vitro cisplatin-induced pyroptosis model was established in MCs. GSDME expression was downregulated using small interfering RNA (siRNA), and caspase-3 activity was inhibited pharmacologically. The critical threshold for pyroptosis induction was determined to be 5 μmol/L cisplatin exposure for 24 h, which activated the caspase-3/GSDME signaling pathway. Results: Cisplatin treatment upregulated GSDME and caspase-3 expression in MCs. Both inhibition of GSDME and pharmacological blockade of caspase-3 significantly attenuated cisplatin-induced cellular damage. Notably, caspase-3 suppression reduced GSDME expression, suggesting a positive regulatory relationship between these mediators. Conclusions: GSDME-mediated pyroptosis plays a pivotal role in cisplatin-induced marginal cell injury, with caspase-3 acting as an upstream regulator of GSDME expression. These findings provide a mechanistic foundation for developing novel therapeutic strategies against cisplatin ototoxicity.

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