Figure 5.

In-depth analysis of HepG2 cytotoxicity using identified VNN paths

(A) Established mechanisms for cell death in drug-induced liver injury. Reactome pathways relevant to the mechanisms are identified and used as reference for the analysis.

(B and C) Survival plots comparing the pathway relevance scores among active (orange curve) versus inactive (gray curve) compounds of two mechanisms of action assays: caspase-3/7 induction (B) and disruption of the mitochondrial membrane potential (C). Comparisons are made for nine cell death-related pathways, with each plot showing the comparison for a single pathway. Red star at the top right denotes that the pathway is related to the respective mechanism of action. Log-rank test is employed to examine whether the two distributions in each plot are significantly different (FDR value shown at the bottom left).

(D) Network diagram showing the simplified DTox structure connecting mifepristone (triangle node) to the HepG2 cytotoxicity (rectangle node) via pathway modules (round nodes). Pathways with relevance score > 0 are colored in purple, with the scale proportional to relevance scale. The VNN paths identified for mifepristone by DTox are shown in solid lines, while the rest are shown in dashed lines.

(E and F) Heatmaps showing the enrichment of nine cell death-related pathways among compounds associated with 20 drug-induced liver injury phenotypes (E) and among compounds of 14 ATC classes (F). Cells are colored based on odds ratio. Fisher’s exact test is employed to examine the significance of enrichment (asterisk denotes FDR < 0.05).

VOD/SOS, veno-occlusive disease and sinusoidal obstruction syndrome.