HSAF-DDI: Heterogeneous Semantic-Aware Drug-Drug Interaction Prediction with Hierarchical Adaptive Fusion

Drug-drug interactions (DDIs) are modulated not only by structural relations between drugs but are also profoundly influenced by underlying biological mechanisms. Most existing methods fail to adequately consider biologically interpretable signals at multiple biological hierarchies, limiting their ability to model the mechanistic complexity of drug-drug interactions. In this paper, we propose a heterogeneous semantic-aware framework (HSAF-DDI) that integrates molecular motif, protein sequence, and knowledge graph representations for DDI prediction. This framework learns local functional semantic representations of molecular motifs, fine-grained target protein semantics that capture deep biological characteristics, and higher-order associations encoded in knowledge graphs. We design a hierarchical adaptive fusion module that facilitates robust fusion and adaptive representation learning over multisource heterogeneous information. In addition, we introduce a contrastive learning mechanism with adversarial negatives and perturbations to improve the discrimination of DDI types and enhance the discriminability and robustness of learned representations. Experiments demonstrate that HSAF-DDI achieves superior overall performance compared to state-of-the-art methods, indicating the critical role of fine-grained biological features in improving the DDI prediction performance.