ATOH8 upregulated by IL-6/STAT3 attenuates endoplasmic reticulum stress and promotes oxaliplatin resistance in gastric cancer

Gastric cancer (GC) is a highly malignant tumor, and oxaliplatin is widely used in its chemotherapy. However, drug resistance limits its clinical effectiveness. This study aimed to identify potential therapeutic strategies to overcome oxaliplatin resistance in GC. RNA sequencing was conducted to compare oxaliplatin-resistant GC cells with their parental counterparts. Using the Limma package, we identified an immunosuppressive microenvironment and six key transcription factors associated with resistance, with ATOH8 showing the most significant correlation with oxaliplatin resistance. Functional assays revealed that ATOH8 expression was linked to increased drug resistance, and its knockout induced upregulation of endoplasmic reticulum (ER) stress-related pathways. Mechanistically, we found that IL-6 facilitated nuclear translocation of STAT3, which subsequently upregulated ATOH8 expression. This established a negative STAT3/ATOH8/ER stress regulatory axis that contributes to chemotherapy resistance. In conclusion, ATOH8 acts as a key regulator of ER stress and chemotherapy resistance in GC. Targeting the STAT3/ATOH8 axis may offer a new therapeutic approach for overcoming resistance in advanced GC.