scFNSA: A Factorized Node-Set Attentive Framework for Single-Cell Multi-Omics Integration.

Single-cell multi-omics technologies enable simultaneous interrogation of transcriptional and epigenomic states at single-cell resolution, providing powerful means to dissect cellular heterogeneity and regulatory mechanisms. However, effective integration of single-cell multi-omics data remains challenging due to extreme sparsity, high dimensionality, and cross-modal heterogeneity, which often lead to distorted similarity structures, information loss, and limited biological interpretability in existing methods. Here, we propose scFNSA, a factorized node-set attentive framework for integrative analysis of single-cell multi-omics data that explicitly decouples modality-specific feature learning from graph-based relational modeling. scFNSA first learns aligned low-dimensional representations for individual modalities through multi-view variational inference and subsequently models complex cellular dependencies via attention-guided graph learning with structured node masking. This design enables robust cross-modal structural alignment while effectively mitigating noise propagation and oversmoothing commonly encountered in deep graph neural networks. Across multiple single-cell multi-omics datasets, scFNSA consistently improves integrative representation quality and cell type resolution compared with state-of-the-art approaches. By decoupling feature extraction from relational inference, scFNSA provides a robust and interpretable framework for single-cell multi-omics integration, facilitating more accurate characterization of cellular states and underlying regulatory landscapes.