Chiisanoside from\nthe Leaves of Acanthopanax\nsessiliflorus Can Resist Cisplatin-Induced Ototoxicity\nby Maintaining Cytoskeletal Homeostasis and Inhibiting Ferroptosis

Ototoxicity is a common side effect of cisplatin cancer\ntreatment,\npotentially leading to hearing loss. This study demonstrated the significant\nprotective activity of Acanthopanax sessiliflorus (A. sessiliflorus) leaves against\ncisplatin-induced ototoxicity (CIO), investigated the active compounds,\nand elucidated their mechanisms in countering CIO. UPLC-Q/TOF-MS analysis\nidentified 79 compounds. Network pharmacology and activity screening\ndetermined that chiisanoside (CSS) plays a crucial role in combating\nCIO. Transcriptomics combined with network pharmacology analysis and\nexperiments revealed that CSS activates the Dock1/PIP5K1A pathway\nto suppress the actin-severing protein gelsolin, protecting hair cells\nfrom cisplatin-induced cytoskeleton damage. CSS also activates the\nSLC7A11/GPX4 pathway via TGFBR2, reducing lipid peroxidation and intracellular\niron accumulation to suppress cisplatin-induced ferroptosis. This\nstudy discovers that the major component CSS in A.\nsessiliflorus leaves reverses CIO by regulating actin\nhomeostasis via Dock1 and inhibiting ferroptosis through TGFBR2, providing\na theoretical basis for expanding CIO treatment targets and related\ndrug development.