SLC7A5-ERBB2 axis drives olaparib resistance via de novo lipid synthesis in ovarian cancer

In the treatment of ovarian cancer, PARP inhibitors such as olaparib have shown promise, yet resistance in advanced cases remains a significant challenge. Our study identified SLC7A5 as a key gene associated with olaparib resistance through differential gene expression and prognostic analysis. High SLC7A5 expression was found to correlate with poor prognosis. In vivo and in vitro experiments revealed that SLC7A5 enhances olaparib resistance by stabilizing ACLY and promoting de novo lipid synthesis via the ERBB2 axis, independent of leucine. Mechanistically, SLC7A5 upregulates ERBB2 transcription through ELK1, and ERBB2 competes with CUL3 to prevent ACLY degradation. These findings suggest that targeting SLC7A5 may reverse olaparib resistance, offering new strategies for combination therapies and improving clinical outcomes in ovarian cancer treatment.