Abstract
Effective drug discovery relies on combining target knowledge with functional assays and multi-omics data to understand chemicals’ molecular actions. However, the relationship between changes in cell morphology and gene expression deregulation over the duration of exposure and across cell lines following chemical exposition remains unclear. To explore this, we analyzed Cell Painting and L1000 data for 106 compounds across three cell lines from osteoblast, lung, and breast tumors (U2OS, A549, and MCF7) at three time points (6 h, 24 h, 48 h) using a 10 μM concentration. Following chemical exposure, we observed significant and specific differences in the spatial organization of cellular structures and components over time and across cell lines in the Cell Painting data, whereas transcriptomic responses showed less pronounced variability. Using Weighted Gene Co-expression Network Analysis (WGCNA) and enrichment analysis, we identified connections between cell morphology and gene deregulation for chemicals with similar biological effects (e.g., HDAC and CDK inhibitors). These findings suggest that while Cell Painting shows distinct patterns, both technologies offer complementary insights into compound-induced cellular changes, enhancing drug discovery and chemical risk assessment.