Despite the global burden of cardiovascular disease, the development of new cardiovascular drugs has stalled for over two decades. The primary reason is intolerance to drug-related side effects. Recently, there has been considerable interest in the development of natural supplements for cardiovascular-protective therapeutics owing to their inherent safety profiles and the clinical evidence for ameliorating chemotherapy-induced cardiovascular complications. However, it remains a huge challenge to understand the cardiovascular-protective mechanisms at the molecular level, which impedes pharmacological optimisation of these bioactive agents for therapeutic use. Therefore, we aim to apply cutting-edge chemoproteomics platforms to understand the intricate signalling interplay in cardiomyocytes in response to different natural products and to construct a comprehensive chemotype database for cardiovascular-protective drug discovery.