• ProTA profiling reveals CFZ-induced changes in stability of 15,000 human proteins, highlighting effects on glycolysis, nitric oxide production, and proteasome subunit homeostasis.
• CFZ synergizes with PI3K/mTOR inhibitors LY294002 and KU-0063794 in multiple myeloma treatment, suggesting combination therapy potential.
• The study provides a systematic understanding of CFZ's mechanism of action, differentiating it from bortezomib and informing rational drug combinations.
• ProTA offers a high-throughput method for studying protein turnover, overcoming limitations of traditional stability assays.