Regulated cell death (RCD) maintains cellular homeostasis and tissue integrity, playing a pivotal role in both health and disease. A variety of RCD subroutines have been identified, each characterized by distinct molecular and morphological features. These cell death modalities do not operate in isolation. Instead, they interact with one another in complex ways. This interaction leads to crosstalk through interconnected and often overlapping signaling pathways. Multiple forms of RCD can coexist within the same disease, influencing various cell types or even the same cell type either synchronously or sequentially. Understanding the intricate dynamics of RCD is of high importance. However, it is challenging to discern the relative contribution of various RCD modalities within the specific biological context. This necessitates the development of advanced methodologies to systematically analyze the priority of RCD pathways in various cellular environments. In the present study, we first created a manually curated collection of gene sets for 18 well-characterized RCD modes. We then estimated the significance of each RCD pathway by combining the results of seven gene set enrichment tests via the Tippet p-value combination approach. Afterward, the consensus of enrichment for each RCD pathway across tests was evaluated using robust rank aggregation. The priorities of RCD were subsequently resolved by considering both the combined p value and the consensus score. The reliability of the proposed approach was validated by applying it to explore the RCD modes in intracranial aneurysms. Finally, a user-friendly web application was created for researchers worldwide. Our study offers a new way to reveal complicated RCD modalities in specific biological settings. The web server is freely accessible at https://www.zhounan.org/rcdrank.
Zhou et al. (Thu,) studied this question.