SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data.

Cells spatially organize into distinct cell types or functional domains through localized gene regulatory networks. However, current spatially resolved transcriptomics analyses fail to integrate spatial constraints and proximal cell influences, limiting the mechanistic understanding of tissue organization. Here, we introduce SpaGRN, a statistical framework that reconstructs cell-type- or functional-domain-specific, dynamic, and spatial regulons by coupling intracellular spatial regulatory causality with extracellular signaling path information. Benchmarking across synthetic and real datasets demonstrates SpaGRN's superior precision over state-of-the-art tools in identifying context-dependent regulons. Applied to diverse spatially resolved transcriptomics platforms (Stereo-seq, STARmap, MERFISH, CosMx, Slide-seq, and 10x Visium), complex cancerous samples, and 3D datasets of developing Drosophila embryos and larvae, SpaGRN not only provides a versatile toolkit for decoding receptor-mediated spatial regulons but also reveals spatiotemporal regulatory mechanisms underlying organogenesis and inflammation.