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Docosahexaenoic acid (DHA) is effective in the prevention and treatment of cancer, congenital disorders, and various chronic diseases. According to the omnigenic hypothesis, these complex diseases are caused by disordered gene regulatory networks comprising dozens to hundreds of core genes and a mass of peripheral genes. However, conventional research on the disease intervention mechanism of DHA only focused on specific types of genes or pathways instead of examining genes at the network level, resulting in conflicting conclusions. In this study, we used HotNet2, a heat diffusion kernel algorithm, to calculate the gene regulatory networks of connectivity map (cMap)-derived agents (including DHA) based on gene expression profiles, aiming to interpret the disease intervention mechanism of DHA at the network level. As a result, significant gene regulatory networks for DHA and 676 cMap-derived agents were identified respectively. The biological functions of the DHA-regulated gene network provide preliminary insights into the mechanism by which DHA intervenes in disease. In addition, we compared the gene regulatory networks of DHA with those of cMap-derived agents, which allowed us to predict the pharmacological effects and disease intervention mechanism of DHA by analogy with similar agents with clear indications and mechanisms. Some of our analysis results were supported by experimental observations. Therefore, this study makes a significant contribution to research on the disease intervention mechanism of DHA at the regulatory network level, demonstrating the potential application value of this methodology in clarifying the mechanisms about nutrients influencing health.

Heat Diffusion Kernel Algorithm-Based Interpretation of the Disease Intervention Mechanism for DHA