Piceatannol protects against age-related hearing loss by inhibiting cellular pyroptosis and inflammation through regulated Caspase11-GSDMD pathway.

Age-related hearing loss (ARHL) is a common issue associated with aging. One of the typical causes of hearing loss is the damage to inner ear hair cells. In addition, oxidative stress and inflammation contribute to ARHL. To avoid excessive inflammatory responses, non-classical scorch death pathway by cell membrane lipopolysaccharide (LPS) activates of caspase-11. Piceatannol (PCT) is also known for anti-tumor, antioxidant and anti-inflammatory effects; however, the protective effect of piceatannol (PCT) on ARHL is unclear. The aim of this study was to elucidate the mechanism underlying protective effect of PCT on ARHL-induced inner ear hair cell damage. In vivo experiments showed that PCT could protect mice from inflammatory aging-induced hearing loss as well as from inner hair cells (IHC) and spiral ganglion (SG) deficits. In addition, inflammatory vesicle inhibitor BAY11-7082 ameliorated ARHL, inhibited NLRP3 and reduced GSDMD expression. In in vitro experiments we used LPS and D-gal to simulate the aging inflammatory environment. The results showed that intracellular reactive oxygen species levels, expression of Caspase-11, NLRP3, and GSDMD were significantly increased, yet treatment with PCT or BAY11-7082 significantly improved HEI-OC-1 cell injury while reducing inflammation-associated protein expression as well as the occurrence of pyroptosis. In conclusion, these results suggest a protective role for PCT against ARHL, possibly through Caspase-11-GSDMD pathway. Our findings may provide a new target and theoretical basis for hearing loss treatment using PCT.