Mapping the Tissue Architecture and Endothelial‐ PEC Network in HAML Using Single‐Cell and Spatial Transcriptomics

ABSTRACT Hepatic angiomyolipoma (HAML) is a rare variant of perivascular epithelioid cell neoplasms (PEComas). Unlike its more common renal angiomyolipoma (RAML), the unique spatial microenvironment of HAML and its specific progression mechanisms remain poorly characterized. Here, we integrated single‐nucleus RNA‐sequencing and spatial transcriptomics from three sporadic HAML cases. We mapped functionally heterogeneous PEComas subpopulations and their localized tissue niches. Transcriptomic alignment and spatial colocalization demonstrated a high similarity between endothelial cells and a subset of PEComas, supporting a potential transition trajectory. Furthermore, spatial intercellular communication analysis identified an endothelial‐derived PDGFD‐PDGFRB axis. We propose that this paracrine signaling engages downstream Ras cascades to sustain localized autophagic flux in adjacent PEComas, potentially acting as a compensatory survival mechanism parallel to intrinsic TSC‐mTOR defects. While definitive in vivo functional fate‐mapping and perturbation studies are requisite, this multi‐omics atlas provides a novel spatial framework for HAML pathogenesis and highlights the endothelial‐PEComa signaling network as a potential therapeutic vulnerability.