You are what you degrade: tracking the cellular fates of the proteasomal degradome

The ubiquitin-proteasome system (UPS) is the primary protein degradation machinery in eukaryotic cells, composed of multiple proteasome isoforms. It plays critical roles in cellular proliferation, metabolism, immune regulation, oxidative stress, and aging, making it a long-standing focus of biological and therapeutic research. Recently, the UPS has been harnessed for the targeted degradation of disease-relevant proteins using proximity-inducing agents such as proteolysis-targeting chimeras and molecular glue degraders, which have transformed our understanding of druggability. Despite these advances, major gaps remain, particularly in understanding the proteasome's functional heterogeneity across biological contexts. Traditional research emphasizes proteasome structure, subunit function, and substrate features to guide chemical tool and therapeutic development. However, an often-overlooked aspect is the proteasomal degradome, the repertoire of peptide fragments generated during protein degradation. These peptides can exhibit biological activities distinct from their parent proteins, and pathogens, including viruses, have evolved mechanisms to block their production to evade immune detection. Thus, degradome characterization is essential to fully appreciate the proteasome's role in shaping cellular phenotypes in both healthy and diseased states. This review highlights recent studies exploring the degradome, with particular attention to -omic technologies applied to profile and interrogate these peptide products. By focusing on degradation outcomes rather than only the machinery, we aim to underscore the importance of tracing proteasome-derived peptides and their biological consequences. Ultimately, this perspective will broaden our understanding of the UPS while suggesting new avenues for therapeutic exploitation beyond current strategies.