Herbal Formula AC591 Protects Against Cisplatin‐Induced Hearing Loss by Inhibiting p53‐Mediated Ferroptosis

Cisplatin is a widely utilized chemotherapeutic agent for the treatment of malignant cancers. However, its clinical application is significantly restricted due to its severe ototoxicity. Therefore, identifying protective medications to prevent cisplatin-induced hearing loss (CIHL) is of paramount importance. Here, we show that AC591, derived from the classical herbal formula "Huangqi Guizhi Wuwu decoction," exhibits notable protective effects on cisplatin-induced ototoxicity. Our findings indicate that pretreatment with AC591 mitigates cisplatin-induced auditory dysfunction, with its mechanism of action linked to the inhibition of p53-mediated ferroptosis. By identifying the active components of AC591 in serum and cochlear tissues following oral administration, we recognized 18β-glycyrrhetinic acid as an effective constituent for hearing protection. Furthermore, we confirmed that 18β-glycyrrhetinic acid exerted otoprotective effects by binding to p53 and regulating proteins associated with ferroptosis. Collectively, our findings suggest that AC591 and 18β-glycyrrhetinic acid may serve as promising agents for preventing CIHL.