Microprotein MP104 Promotes Malignant Progression of Colorectal Cancer Through Regulating Protein Translation

Colorectal cancer (CRC) remains a major cause of cancer mortality, necessitating the identification of novel oncogenic drivers. We report the discovery of MP104, a 104-amino acid microprotein encoded by the long non-coding RNA ZEB1-AS1, 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 AMPKα2 ubiquitination and degradation, thereby activating mTOR signaling. This activation enhances EIF4B phosphorylation and stability, while MP104 further inhibits RNF40-mediated EIF4B ubiquitination, collectively sustaining translational upregulation. Thus, MP104 drives CRC progression primarily through reprogramming protein translation via the UBE2O-AMPKα2-mTOR-EIF4B axis, establishing it as a key regulator of oncogenic translational control and a promising biomarker and therapeutic target in CRC.