Dysregulated inflammation/immune response has been identified as a key factor driving major human diseases such as cancer, Rheumatoid Arthritis (RA), Type 2 diabetes (T2D) and Alzheimer's disease (AD). However, there lacks a comprehensive comparative study of the inflammation/immune response components (inflammatome) in those diseases for identifying more effective targets and therapeutics against multiple inflammation driven diseases. This concept proposal aims to systematically investigate the uniqueness and commonality of inflammation related pathways in major human diseases using state-of-the-art multiscale molecular network modeling approaches to integrate large-scale multi-Omics datasets generated by NIH's AMP Programs and other sources. This project will identify not only data driven signatures, networks and key drivers of inflammation conserved across multiple diseases, but also FDA approved drugs that are potentially effective in treating multiple inflammatory diseases. The proposed study is truly transformative in discovering both novel mechanisms and therapeutics for major human diseases which involve dysregulated inflammation and immune response.