GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL

Inflammation is among the known causes of cisplatin-induced hearing loss
(CIHL), but its exact pathophysiological mechanisms remain unclear.
Herein, we demonstrated that pyroptosis—a recently identified inflammatory
type of regulated cell death dependent on gasdermin D (GSDMD)—was
activated in the cochleae of cisplatin-treated mice, causing CIHL.
Meanwhile, treatment with the GSDMD inhibitor necrosulfonamide alleviated
CIHL in these mice. To further examine the role of GSDMD-mediated
pyroptosis in CIHL, we conducted experiments in Gsdmd-deficient
mice. Gsdmd−/− mice demonstrated significantly lower cisplatin-induced
cochlear damage than control mice and appeared to be invulnerable to CIHL.
Furthermore, GSDMD-mediated pyroptosis in the stria vascularis (SV), but
not in the hair cells (HCs), played a dominant role in CIHL. In marginal
cells (MCs) of SV, cisplatin induced caspase-dependent GSDMD cleavage, and
the pore-forming N-terminal of GSDMD rapidly localized to the
mitochondria, leading to abnormal mitochondrial aggregation and oxidative
stress. The consequent mitochondrial dysfunction in MCs might result in
the severe progression of inflammation, SV damage, and HC loss. Notably,
the pharmacological inhibition of pyroptosis using the FDA-approved drug
disulfiram effectively alleviated the symptoms of CIHL. Collectively,
these findings offer a broad avenue for inhibiting pyroptosis-induced
cisplatin ototoxicity and provide valuable theoretical insights for the
clinical management of CIHL.