Background <p>Carboplatin is a commonly utilized chemotherapy agent for breast cancer treatment, yet resistance to this drug remains a significant clinical challenge</p> Objective <p>The objective of this study was to investigate the role and regulatory mechanism of zinc finger protein 468 (ZNF468) in carboplatin resistance in breast cancer.</p> Methods <p>To establish carboplatin-resistant cells, SK-BR-3 and MDA-MB-231 cells were exposed to increasing concentrations of carboplatin. ZNF468 expression was analyzed in clinical samples (carboplatin-resistant vs. sensitive patients, n=40) and carboplatin-resistant cells. Functional assays, including Cell Counting Kit-8 (CCK-8), EDU staining, flow cytometry, and colony formation assays, were conducted to evaluate cell viability and apoptosis. The interactions and underlying mechanisms were further explored using Chromatin immunoprecipitation (ChIP), luciferase reporter assays, co-immunoprecipitation (Co-IP), and cycloheximide chase assays.</p> Results <p>ZNF468 was significantly elevated in carboplatin-resistant cells and tissues. Knockdown of ZNF468 reduced the growth of cells and increased apoptosis in drug-resistant cells. ZNF468 was found to transcriptionally activate X-linked inhibitor of apoptosis protein (XIAP), which contributed to enhanced resistance to apoptosis and carboplatin. In addition, RING Finger Protein 4 (RNF4) was shown to stabilize ZNF468 by promoting its phosphorylation, and this stabilization further aggravated the resistance to apoptosis and carboplatin treatment in breast cancer cells.</p> Conclusion <p>RNF4 stabilized ZNF468, which transcriptionally activates XIAP, enhancing resistance to apoptosis and promoting carboplatin resistance in breast cancer. This study highlights the critical role of ZNF468 in carboplatin resistance, providing potential therapeutic targets for overcoming drug resistance in breast cancer treatment.</p>