<p>Background Ribociclib, a CDK4/6 inhibitor, is a targeted therapy for breast cancer management. However, acquired resistance to ribociclib is a common clinical challenge. This study aimed to investigate the role of LEM-Domain Protein 4 (LEM4), a nuclear envelope protein, in mediating ribociclib resistance in breast cancer cells and elucidate the underlying molecular mechanisms. Methods LEM4 expression was analyzed in breast cancer patient samples and cell lines. Ribociclib-resistant MCF-7 and T47D cell lines were established, and the effects of LEM4 knockdown on drug sensitivity, apoptosis, and β-catenin signaling were evaluated using in vitro cytotoxicity, co-immunoprecipitation, β-catenin transcription activity and in vivo tumor formation assays. Results LEM4 was found to be overexpressed in breast cancer tissues and cell lines, and its high expression correlated with worse overall survival in patients. Ribociclib-resistant breast cancer cells demonstrated significantly elevated LEM4 expression levels, and LEM4 silencing re-sensitized drug-resistant cells to ribociclib-induced cytotoxicity and apoptosis in vitro and in vivo. Mechanistically, LEM4 interacted with β-catenin, increasing its protein stability, nuclear translocation, and transcriptional activity. Inhibition of β-catenin signaling reversed ribociclib resistance. Conclusion This study identifies LEM4 as a key mediator of ribociclib resistance in breast cancer cells through its interaction with β-catenin and subsequent activation of β-catenin signaling. Targeting the LEM4/β-catenin axis represents a potential therapeutic strategy to overcome ribociclib resistance in breast cancer. </p>