Abstract Understanding biological pathways requires more than static diagrams. We present WayFindR, an R package that converts pathway data from WikiPathways and KEGG into graph structures using igraph, enabling computational analysis of regulatory features such as negative feedback loops. Rooted in control theory, negative feedback is essential for system stability, yet it is often underrepresented in curated pathway data. In this study, we systematically analyzed pathway information from both databases across multiple species and found that feedback loops—particularly negative ones—are rarely captured. This gap likely reflects both biological and technical challenges. Biologically, feedback mechanisms are inherently complex and often remain uncharted due to limited experimental focus. Technically, pathway databases frequently lack standardized annotations and complete representations of regulatory interactions, especially inhibitory edges that are crucial for identifying feedback. These observations underscore the need for improved data curation and consistent annotation practices to enhance our understanding of regulatory dynamics. By bridging the gap between static pathway diagrams and dynamic system-level insights, WayFindR enables reproducible and scalable investigation of feedback regulation in cellular networks. The WayFindR R package can be downloaded from the Comprehensive R Archive Network (https://cran.r-project.org/web/packages/WayFindR/index.html). The processed data along with code for download can be accessed via the GitLab repository (https://gitlab.com/krcoombes/wayfindr).
Bombina et al. (Fri,) studied this question.