Degradomics turns TPD into systems pharmacology

Targeted protein degradation (TPD) has reshaped drug discovery by enabling small molecules, including proteolysis-targeting chimeras and molecular glues, to eliminate disease-relevant proteins rather than simply inhibit their activity. This event-driven mechanism creates a new analytical problem: binding alone does not reveal whether a target is productively degraded, whether neosubstrates are induced, or whether downstream proteome changes reflect direct mechanism, cellular stress, or toxicity. Degradomics provides the systems-level readout needed to interpret these effects. By integrating quantitative proteomics, data-independent acquisition, tandem mass tag workflows, ubiquitin-remnant profiling, and proximity-labeling approaches, degradomics can connect ternary-complex formation with ubiquitination, protein loss, selectivity, resistance, and translational response. However, degradomics is not a neutral checklist. Prolonged treatment, low-abundance substrate detection bias, cytotoxicity, cell-cycle effects, and technical noise in ubiquitinome enrichment can mislead interpretation if experiments lack appropriate time courses, orthogonal validation, and cellular-state controls. This Commentary argues that degradomics should be treated not as a late-stage quality-control assay, but as a systems pharmacology layer for TPD discovery. Used carefully, it can expose neosubstrates, guide degrader optimization, support pharmacodynamic biomarker development, and help transform TPD from empirical screening into a more predictive therapeutic discipline.