Cytoscape files of pathway enrichment analyses and PPI mapping associated with manuscript NCOMMS-22-32085A Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation Anna Rodina1,11, Chao Xu1,11, Chander S. Digwal1,11, Suhasini Joshi1,11, Anand R. Santhaseela1, Sadik Bay1, Swathi Merugu1, Aftab Alam1, Pengrong Yan1, Chenghua Yang1,12, Tanaya Roychowdhury1, Palak Panchal1, Liza Shrestha1, Yanlong Kang1, Sahil Sharma1, Yogita Patel2, Justina Almadovar1, Adriana Corben3,13, Mary Alpaugh1,14, Shanu Modi4, Monica L. Guzman5, Teng Fei6, Tony Taldone1, Stephen D. Ginsberg7,8, Hediye Erdjument-Bromage9, Thomas A. Neubert9, Katia Manova-Todorova10, Jason C. Young2, Meng-Fu Bryan Tsou10, Tai Wang1,*, Gabriela Chiosis1,4,* Abstract Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of first-in-class chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.