Liver malignant tumors (LMTs) have recently been reported as severe and life-threatening adverse drug events associated with drug-induced liver injury (DILI). DILIs are the most common adverse drug event and can cause the withdrawal of medicinal products or major regulatory action. To reduce the attrition rate and cost of drug discovery, various quantitative structure-toxicity relationship models have been proposed to predict the probability of a DILI based on the chemical structure of a drug.

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... owever, there are many unresolved issues regarding the predictors of LMT-inducing drugs, and biologically interpretable prediction models for LMT have not been developed. Here, we constructed prediction models for whether a drug is LMT-inducing based on the activity of molecular initiating events (MIEs), which are biologically interpretable features and are defined as the initial interaction between a molecule and biosystem. We then constructed five machine learning models (i.e., LightGBM, XGBoost, random forest, neural network, and support vector machine) and evaluated their predictive performances. LightGBM achieved the best performance among the tested models. The MIEs making the highest contribution to the model construction for drug-induced LMT were inducement of Enhanced Level of Genome Instability Gene 1 (human ATAD5), nuclear factor-κ B, and activation of thyrotropin-releasing hormone receptor. These results support the previous literature and can be related to the mechanism onset of drug-induced LMT. Our findings may provide useful knowledge for drug development, research, and regulatory decision-making and will contribute to building more accurate and meaningful DILI prediction models by increasing understanding of biological predictors.