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In this study, it is shown that eEF2K is highly expressed in TNBC and is associated with poor prognosis. In vitro, in vivo, and patient\u2010derived organoid experiments demonstrate that knockdown of eEF2K significantly impedes progression of TNBC. Proteomic analysis and confirmation experiments reveal that eEF2K positively regulates the mRNA and protein expressions of sex\u2010determining region Y\u2010box 8 (SOX8). Mechanistically, eEF2K binds to and phosphorylates aurora kinase A (AURKA) at S391, a newly identified phosphorylation site critical for maintaining AURKA protein stability and kinase activity. Moreover, the compound C1, a molecular glue to degrade eEF2K, is optimized by designing and synthesizing its derivatives using reasonable structure\u2010based optimization approach. The new compound C4 shows\u00a0 better ability to degrade eEF2K and stronger anti\u2010cancer activity than C1. These findings not only uncover the pivotal role of the eEF2K\/AURKA\/SOX8 axis in TNBC progression, but also provide a promising lead compound for developing novel drug for treatment of TNBC.<\/jats:p>","DOI":"10.1002\/advs.202412985","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T08:49:16Z","timestamp":1739522956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of a Novel Substrate for eEF2K and the AURKA\u2010SOX8 as the Related Pathway in TNBC"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiaoya","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Pharmacy The Second Xiangya Hospital Central South University  Changsha 410011 China"},{"name":"Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug  Changsha 410011 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