The Double-Edged Sword: Legumain as a Context-Dependent Mediator and Therapeutic Target in Cancer and Cardiovascular Disease

Legumain, an asparaginyl endopeptidase, has emerged as a critical cysteine protease with diverse and complex roles in human health and disease. While traditionally known for its function in endolysosomal protein degradation, a growing body of evidence has revealed its presence in multiple cellular compartments and its involvement in a vast array of pathological processes. This review provides a comprehensive synthesis of the current literature, bridging the often-siloed research in oncology and cardiovascular medicine to present a unified view of legumain’s function. We first detail the multifaceted role of legumain in cancer, where it acts as a driver of tumour proliferation, invasion, and metastasis. We explore its function as a modulator of the tumour microenvironment, particularly its ability to polarise macrophages towards an immunosuppressive phenotype, and discuss its emerging value as a candidate prognostic biomarker and a versatile therapeutic target. Notably, however, therapeutic targeting of legumain remains predominantly at the preclinical stage. Subsequently, we examine its significant contribution to cardiovascular diseases, detailing its mechanistic involvement in promoting atherosclerosis, hypertension, and adverse cardiac remodelling through pathways involving inflammation, extracellular matrix turnover, and immune cell modulation. By synthesising these findings, we highlight the convergent pathological mechanisms, discuss current controversies and methodological limitations—such as the lack of standardised assays—and propose key future directions. This review frames legumain as a biological rheostat and a potentially important node in chronic disease, underscoring its potential as a powerful biomarker and a sophisticated therapeutic target across a broad spectrum of human pathologies.