Spatial transcriptomics identifies the molecular and disease landscapes of adult human hypothalamus

Human hypothalamus is central to basic physiological functions and its dysfunction is associated with many diseases, yet its spatial cellular and molecular architecture remains poorly understood. Here we present a comprehensive 3D atlas of the adult human hypothalamus aligned to magnetic resonance imaging (MRI) data, integrating spatial transcriptomics, single-nucleus RNA sequencing, and histological analysis. Cross-species comparisons identified homologous regions and subregions between human and mouse hypothalamus. We found that adult human hypothalamus maintained a conserved spatial pattern of transcription factors along the anteroposterior axis established during early development. Furthermore, we uncovered a more segregated neuronal organization in human hypothalamus than mouse and distinctive human features in various hypothalamic nuclei. Finally, we identified the disease landscape in human hypothalamus. Together, our atlas revealed the spatial cellular and molecular organization of the human hypothalamus, helping to bridge experimental animal studies and human clinical investigation.