Abstract Motivation Identifying non-coding RNAs (ncRNAs) associated with drug resistance is critical for elucidating molecular mechanisms underlying drug response, facilitating drug screening, and discovering novel therapeutic targets. While several graph neural network-based methods have been proposed to infer ncRNA-drug resistance associations, they remain fundamentally constrained by semantic distortion induced by sparse bipartite network and neglect of relational semantics among molecular entities, ultimately compromising both predictive reliability and biological interpretability. Results In this study, we propose iNcRD-HG, a novel framework for identifying ncRNA-drug resistance associations. The framework addresses three critical aspects: constructing a context-enriched heterogeneous network that integrates six distinct molecular interaction types with bio-entity-specific attributes, developing a semantic-enhanced graph learning architecture that implements relation-type-aware message passing to capture complex contextual dependencies, and introducing an interpretability mechanism to reveal potential synergistic pathways underlying drug response. Experimental results demonstrate that iNcRD-HG achieves superior predictive performance across diverse benchmark datasets while deriving association features with strong discriminative capability. By identifying molecular synergistic contexts, iNcRD-HG provides mechanistically interpretable insights into ncRNA-mediated drug resistance. Availability and Implementation Datasets and source codes are available at https://github.com/Biohang/iNcRD-HG. Supplementary information Supplementary data are available at Bioinformatics online.
Wei et al. (Tue,) studied this question.