Paeoniflorin attenuates cisplatin induced ototoxicity by inhibiting ferroptosis mediated by HMGB1/NRF2/GPX4 pathway.

Cisplatin-induced ototoxicity is a major dose-limiting complication in cancer therapy, profoundly diminishing quality of life. Paeoniflorin (PAE), a bioactive compound from Paeonia lactiflora, exhibits diverse pharmacological activities. This study aimed to evaluate the efficacy of PAE in countering cisplatin-induced ototoxicity and explore its molecular mechanisms. Cochlear hair cell injury models were established both in vitro and in vivo using cisplatin. Ferroptosis was induced in HEI-OC1 cells with RSL3, and HMGB1-overexpressing models were constructed to investigate its role. The findings indicated that PAE effectively alleviated cisplatin-induced hearing loss and cochlear cell damage in both in vitro and in vivo models. Moreover, PAE significantly mitigated the inflammatory response triggered by cisplatin exposure. Mechanistically, PAE reduced oxidative stress and ferroptosis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Notably, PAE directly interacted with HMGB1 and suppressed its expression, thereby inhibiting HMGB1-mediated ferroptosis in cochlear cells. This study highlights PAE as a promising therapeutic candidate for preventing cisplatin-induced ototoxicity. By elucidating the role of PAE in modulating ferroptosis through HMGB1 and the NRF2/SLC7A11/GPX4 pathway, our findings provide new insights into potential strategies for mitigating cisplatin-induced hearing loss.