Comprehensive analysis of regulated cell death pathways: intrinsic disorder, protein–protein interactions, and cross-pathway communication

Abstract

Regulated cell death (RCD) pathways—once viewed as linear, independent processes—are now recognized as components of a dynamic, interconnected molecular network that dictates cellular fate in health and disease. This study presents a systematic meta-analysis of thirteen major RCD pathways, examining their molecular mechanisms, triggers, and interconnections through protein–protein interaction (PPI) networks. Using custom bioinformatics approaches, we unveiled the interactome of proteins involved in apoptosis, autophagy-dependent cell death, cellular senescence, mitotic catastrophe, entotic cell death, ferroptosis, cuproptosis, immunogenic cell death, lysosome-dependent cell death, mitochondrial permeability transition-driven necrosis, necroptosis, neutrophil extracellular trap formation-related cell death (NETosis), parthanatos, and pyroptosis. By integrating data from an extensive literature review with STRING database analyses, we identified previously unrecognized cross-pathway interactions and regulatory nodes where special attention was given to the role of intrinsically disordered proteins (IDPs) in these pathways. Our findings reveal a complex interplay between different RCD mechanisms and highlight potential therapeutic targets for diseases characterized by dysregulated cell death programs, including cancer and autoimmune disorders. This comprehensive analysis provides new insights into the molecular architecture of RCD pathways and their cooperative functions in maintaining cellular homeostasis.