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We report the discovery of MP104, a 104\u2010amino acid microprotein encoded by the long non\u2010coding RNA ZEB1\u2010AS1, which is endogenously expressed and upregulated in CRC with strong association to poor prognosis. Functional assays revealed that MP104 promotes CRC cell proliferation, migration, invasion, and metastasis. Mechanistically, MP104 interacts with UBE2O to facilitate AMPK\u03b12 ubiquitination and degradation, thereby activating mTOR signaling. This activation enhances EIF4B phosphorylation and stability, while MP104 further inhibits RNF40\u2010mediated EIF4B ubiquitination, collectively sustaining translational upregulation. Thus, MP104 drives CRC progression primarily through reprogramming protein translation via the UBE2O\u2013AMPK\u03b12\u2013mTOR\u2013EIF4B axis, establishing it as a key regulator of oncogenic translational control and a promising biomarker and therapeutic target in CRC.<\/jats:p>","DOI":"10.1002\/advs.76593","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:47:30Z","timestamp":1784807250000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microprotein MP104 Promotes Malignant Progression of Colorectal Cancer Through Regulating Protein Translation"],"prefix":"10.1002","volume":"13","author":[{"given":"Fang","family":"Chen","sequence":"first","affiliation":[{"name":"Cancer Institute Cellular Therapeutics School of Medicine Xuzhou Medical University  Xuzhou Jiangsu China"},{"name":"Department of Laboratory Medicine Affiliated Hospital of Xuzhou Medical University  Xuzhou 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