scKAN: Interpretable Single-cell Analysis for Cell-type-specific Gene Discovery and Drug Repurposing via Kolmogorov-Arnold Networks

Abstract

Single-cell analysis has revolutionized our understanding of cellular heterogeneity, yet current approaches face challenges in efficiency and interpretability. In this study, we present scKAN, a framework that leverages Kolmogorov-Arnold Networks for interpretable single-cell analysis through three key innovations: efficient knowledge transfer from large language models through a lightweight distillation strategy; systematic identification of cell-type-specific functional gene sets through KANs learned activation curves; and precise marker gene discovery enabled by KANs importance scores with potential for drug repurposing applications. The model achieves superior performance on cell-type annotation with a 6.63% improvement in macro F1 score compared to state-of-the-art methods. Furthermore, scKANs learned activation curves and importance scores provide interpretable insights into cell-type-specific gene patterns, facilitating both gene set identification and marker gene discovery. We demonstrate the practical utility of scKAN through a case study on pancreatic ductal adenocarcinoma, where it successfully identified novel therapeutic targets and potential drug candidates, including Doconexent as a promising repurposing candidate. Molecular dynamics simulations further validated the stability of the predicted drug-target complexes. Our approach offers a comprehensive framework for bridging single-cell analysis with drug discovery, accelerating the translation of single-cell insights into therapeutic applications.