Critical nodes discovery in pathophysiological signaling pathways

Network-based ranking methods (e.g. centrality analysis) have found extensive use in systems medicine for the prediction of essential proteins, for the prioritization of drug targets candidates in the treatment of several pathologies and in biomarker discovery, and for human disease genes identification. Here we propose to use critical nodes as defined by the Critical Node Problem for the analysis of key physiological and pathophysiological signaling pathways, as target candidates for treatment and management of several cancer types, neurologic and inflammatory dysfunctions, among others. We show how critical nodes allow to rank the importance of proteins in the pathways in a non-trivial way, substantially different from classical centrality measures. Such ranking takes into account the extent to which the network depends on its key players to maintain its cohesiveness and consistency, and coherently maps biologically relevant characteristics that can be critical in disease onset and treatments.