The adipokine apelin has been directly implicated in various physiological processes during embryogenesis and human cancers. Nevertheless, the importance of the conversion of its precursor proapelin to mature apelin in tumorigenesis remains unknown. In this study, we identify Furin as the cellular proprotein convertase responsible for proapelin cleavage. We explore the therapeutic potential of targeting proapelin cleavage sites in metastatic colorectal cancer by introducing apelin-dm, a modified variant resulting from alteration in proapelin cleavage sites. Apelin-dm demonstrates efficacy in inhibiting tumor growth, promoting cell death, suppressing angiogenesis, and early colorectal liver metastasis events. Proteomic analysis reveals reciprocal regulation between apelin and apelin-dm on proteins associated with clinical outcomes in colon cancer patients. Apelin-dm emerges as a modulator of apelin receptor dynamics, influencing affinity, internalization, and repression of apelin signaling linked to various protein kinases. Pharmacokinetic and toxicity assessments confirm the specificity, safety, and stability of apelin-dm, as well as its facile hepatic metabolism. These findings position targeting proapelin cleavage as a promising therapeutic strategy against metastatic colorectal cancer, paving the way for further clinical exploration.