Deciphering radiopharmaceutical mechanisms through integrated proteomic and PTM-proteomic profiling†

Drug-regulated protein post-translational modifications (PTMs) enable the identification of modulated pathways and the revelation of phenotypic responses in diseases. However, the integrated regulatory mechanisms of radiopharmaceuticals across the proteomic and PTM landscapes remain poorly characterized. To address this gap, this study presents a quantitative multi-level proteomic analysis to assess regulated PTMs and pathway engagement. Quantitative glycoproteomics, phosphoproteomics, and global proteomics were performed using tumor tissues from radiopharmaceutical-treated mouse models. By analyzing subcellular signaling pathways with site-specific PTMs, differentially expressed molecular signatures were identified with radiopharmaceutical action. Our study provides a comprehensive landscape of the global proteome and PTM-proteome for radiopharmaceutical regulation. These findings uncover multi-level cellular molecular mechanisms involving DNA repair, extracellular matrix organization, and metabolic regulation. These findings elucidate the molecular mechanism of radiopharmaceuticals at the proteomic and PTM-proteomic levels, offering valuable insights for radiopharmaceutical development.