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

ABSTRACT 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.