Fig. 3: Three Cox2-inhibitors with the same target but distinct DILI profiles.
From: A large-scale human toxicogenomics resource for drug-induced liver injury prediction
A Valdecoxib, deemed safe, is predicted no DILI risk across all dose levels, with a margin of safety (MOS) greater than 300. B Sulindac, associated with idiosyncratic DILI, and Lumiracoxib, withdrawn from the market due to severe liver failure, are both flagged as high-risk by the model with MOS values of 31 and 1, respectively. C The predictions are driven by pathways implicated in DILI. Differential pathway signatures highlight key mechanisms underlying DILI risk, include oxidative stress, drug metabolism, receptor-mediated signaling, fat and cholesterol synthesis, and bile acid regulation. Pathway enrichment was performed using Enrichr (gseapy), based on a Fisher’s exact test with Benjamini–Hochberg correction. Color intensity reflects –log10 adjusted p-values. D Dose-resolved DILI risk probabilities illustrate how increasing dosages impact the likelihood of liver injury. Dots indicate mean predictions and blue shaded confidence intervals represent the standard deviations across ensemble models. These predictions align closely with clinical outcomes, demonstrating its utility in DILI risk stratification, pathway-based mechanistic understanding, and guiding safer drug development.
