Metformin alleviates presbycusis by activating the SIRT1/PINK1/GPX4 pathway in vitro and in vivo.

Abstract

BACKGROUND: Presbycusis is a neurodegenerative disease associated with chronic inflammation. Metformin is an anti-inflammatory agent used to treat diabetes. However, its efficacy in delaying presbycusis has not been established. AIM: The study aimed to investigate the protective effects of metformin against presbycusis and elucidate its mechanistic role in modulating the SIRT1/PINK1/GPX4 signaling pathway in vitro and in vivo. MATERIALS AND METHODS: The target genes of presbycusis were identified using bioinformatics. The HEI-OC1 cells were subsequently induced with D-galactose (D-gal) and co-treated with metformin in vitro. Their viability, mitochondrial function, and molecular markers were subsequently monitored. Meanwhile, C57BL/6J mice were injected with metformin, and their auditory brainstem response (ABR) thresholds were assessed by ABR test. Animal histopathological examination, immunofluorescence staining, and western blotting were used to assess the protective effects of metformin against presbycusis in mice. RESULTS: Metformin increased the viability of senescent auditory cells, enhanced mitochondrial function by reducing reactive oxygen species production, and inhibited ferroptosis in vitro. It also improved the auditory function of C57BL/6J mice, reduced their cochlear concentrations of Feand malondialdehyde, and prolonged their hair cell survival in vivo. Metformin upregulated SIRT1, PINK1, and GPX4 in vitro and in vivo. CONCLUSION: Metformin activates the SIRT1/PINK1/GPX4 signaling pathway, and it may be effective for treating presbycusis.