lncAPNet enables the deciphering of lncRNA–mRNA connections in patient transcriptomic data

Long non-coding RNAs (lncRNAs) regulate gene expression through chromatin remodeling, transcriptional control, and post-transcriptional modulation, influencing physiological cell homeostasis but also disease onset. Yet most transcriptomic and network-based studies rely on descriptive linear co-expression analyses, missing nonlinear and mechanistic insights. Emerging ML/DL methods offer promise but remain limited by data sparsity, noise, insufficient biological priors, and poor interpretability, constraining systems-level lncRNA-mRNA motif discovery. In this manuscript, we introduce lncAPNet, an extended version of APNet workflow, which integrates graph-based nonlinear inference of lncRNA–mRNA interactions using NetBID2’s activity logic within an lncRNA-focused SJARACNe co-expression network, coupled with PASNet, a biologically informed sparse deep learning model. This framework enables explainable identification of lncRNA drivers in two different cancer type case studies, Chronic Lymphocytic Leukemia (CLL) and Prostate Adenocarcinoma (PRAD), uncovering lncRNA drivers that illuminate lncRNA-mediated programs in cancer progression. lncAPNet’s R scripts, Python scripts, and methodologies are available at github repository: https://github.com/BiodataAnalysisGroup/lncAPNet