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Cyclin\u2010dependent kinase 4\/6 inhibitors (CDK4\/6i) have become a crucial therapeutic approach for this type of cancer. However, ER+ breast cancer frequently develops resistance to CDK4\/6i, limiting therapeutic efficacy. Alternative splicing is a key post\u2010transcriptional regulatory mechanism that may drive such resistance. In this review, we comprehensively analyzed the literature on the molecular mechanisms and key signaling pathways associated with CDK4\/6i resistance in ER+ breast cancer and introduced the role of alternative splicing, with a particular focus on its function in tumor drug resistance. Available evidence suggests that splicing dysregulation may influence resistance through multiple pathways, including cell\u2010cycle control, epithelial\u2010mesenchymal transition, growth factor and RAS\/MAPK signaling, and immune\u2010related programs. Recent work has also suggested that reduced expression of the splicing regulator NSRP1 may be associated with CDK4\/6i resistance through altered NSD2 splicing and activation of interferon signaling, although this mechanism currently requires further independent validation. Collectively, these findings support alternative splicing as a promising but still evolving area of investigation in CDK4\/6i resistance. This work provides deeper insights into the role of alternative splicing in CDK4\/6i resistance and offers a theoretical foundation for developing novel therapeutic approaches. Future research may focus on developing drugs that precisely modulate specific splicing events or combining CDK4\/6i with splicing modulators to reverse or delay resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ddr.70354","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:06:04Z","timestamp":1786377964000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alternative Splicing in Cyclin\u2010Dependent Kinase 4\/6 Inhibitor Resistance in Estrogen Receptor\u2010Positive Breast Cancer"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6862-912X","authenticated-orcid":false,"given":"Yuqiu","family":"Cui","sequence":"first","affiliation":[{"name":"School of Medicine (Institute of Translational Medicine) Yangzhou University Yangzhou China"},{"name":"Jiangsu Key Laboratory of Noncoding RNA Fundamental and Clinical Translational 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