MNAT1 in gastrointestinal cancers: mechanistic insights and therapeutic strategies-a narrative review.

BACKGROUND AND OBJECTIVE: Ménage à trois 1 (MNAT1) is an essential scaffolding subunit of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex and has been increasingly implicated in cancer pathogenesis. Given the accumulating evidence linking MNAT1 to gastrointestinal (GI) malignancies, this narrative review aims to summarize current knowledge regarding the biological functions, oncogenic roles and therapeutic potential of MNAT1 in GI cancers. METHODS: A literature search of the relevant databases (PubMed, Web of Science) was conducted, with a focus on recent and key publications in the English language. The search strategy included terms related to MNAT1, GI cancer, CAK complex and therapeutic targeting. KEY CONTENT AND FINDINGS: MNAT1 stabilizes the CAK complex and promotes cell-cycle progression by enabling CAK-mediated T-loop phosphorylation of cell-cycle CDKs. In addition, CAK functions as a module of the general transcription factor II H (TFIIH) and supports phosphorylation of RNA polymerase II (Pol II) at active promoters, sustaining oncogenic transcription programs. Therapeutic strategies that target MNAT1/CAK include CDK7 inhibition and CAK complex degradation, both of which can suppress transcriptional output and induce cell-cycle arrest. Combination regimens incorporating MNAT1/CAK targeting have also shown preclinical efficacy. CONCLUSIONS: This review summarizes current evidence on MNAT1 across multiple malignancies, with a focus on gastrointestinal cancers. We discuss MNAT1 as a potential biomarker for prognosis and treatment response and highlight opportunities and challenges for therapeutically targeting MNAT1/CAK in gastrointestinal cancer.