Pinoresinol Diglucoside Attenuates Nuclear Receptor Coactivator 4‐Mediated Ferritinophagy Associated with Cisplatin‐Induced Hearing Loss

Cisplatin can cause irreversible hearing loss. However, effective approaches to its prevention are not established. In this study, the effect of the traditional Chinese medicine monomer pinoresinol diglucoside (PDG) is evaluated on cisplatin-induced ototoxicity and its underlying mechanism of action. PDG significantly increases cell viability and inhibits reactive oxygen species production and ferroptosis in cisplatin-treated House Ear Institute-Organ of Corti 1 cells and basilar membranes. PDG partially restores hearing loss caused by cisplatin. Transcriptome sequencing identifies Suppressor of Cytokine Signaling 1 (SOCS1), which is significantly elevated in the cisplatin-only group but significantly reduced after PDG application. SOCS1 is a ferroptosis-promoting factor, and knocking it down significantly inhibits nuclear receptor coactivator 4 (NCOA4) and inhibits ferritinophagy. Transmission electron microscopy reveals that knocking down SOCS1 reduces the number of autophagic lysosomes induced by cisplatin. Co-immunoprecipitation is performed to confirm the interaction between SOCS1 and NCOA4. Taken together, these results indicate that PDG inhibits NCOA4-mediated ferritinophagy by downregulating SOCS1, which reduces cisplatin-induced ototoxicity. This study provides a new clinical option for the prevention of cisplatin-induced hearing loss.