ESM1 drives cisplatin resistance and ferroptosis resistance via ERBB2/FAK/SRC/HSPB1/NF-κB signaling in ovarian cancer

<h2>Summary</h2> Cisplatin stands as a highly effective chemotherapeutic agent for ovarian cancer (OC); yet, the development of resistance to it poses a significant clinical challenge. In this study, we utilized prior RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) data to identify downstream genes and interacting proteins altered following ESM1 knockdown, and further confirmed the impact of these changes on ferroptosis and cisplatin resistance in OC cells through electron microscopy and various molecular biology experiments. Additionally, public databases, tissue microarrays, and multiplex immunofluorescence staining were employed to assess the prognostic value of genes like ESM1 for OC patients. The results demonstrate that HSPB1 acts as a pivotal gene in ESM1-mediated cisplatin and ferroptosis resistance. Mechanistically, ESM1 binds to ERBB2 to promote HSPB1 transcription, thereby activating the FAK/SRC and NF-κB pathways, which ultimately inhibits ferroptosis and enhances cisplatin resistance in OC. Collectively, these findings elucidate a regulatory mechanism by which ESM1 drives cisplatin and ferroptosis resistance via the ERBB2/FAK/SRC/HSPB1/NF-κB axis in ovarian cancer.