Mapping the hepatic neural niche: from three-dimensional innervation architecture to periportal interoception and human translation.

The liver has traditionally been viewed as an organ regulated by circulating hormones and long-range autonomic reflexes, with its intrahepatic neural architecture receiving comparatively little systematic attention. However, recent advances in tissue clearing, three-dimensional (3D) volumetric imaging, neural tracing, and spatial omics are reshaping this view. Here we synthesize emerging evidence that the hepatic nervous system is organized around spatially defined neurovascular-cellular niches, and propose the periportal region as a dominant anatomical site for interoceptive integration, while acknowledging contributions from other hepatic compartments. We introduce a conceptual framework built on three spatial axes-hilum-to-periphery, portal-to-central, and neurovascular-cellular proximity-to replace the traditional binary distinction between portal tract and parenchymal innervation. We critically examine why conventional two-dimensional histology has systematically underestimated the complexity of hepatic innervation and evaluate how 3D imaging technologies are resolving long-standing controversies, particularly regarding the existence and extent of parasympathetic parenchymal innervation. We further review how chronic liver diseases, including metabolic dysfunction-associated steatohepatitis, fibrosis, and cholestasis, remodel the neural niche through spatially defined degenerative and regenerative processes. A dedicated cross-species analysis identifies fundamental anatomical, methodological, and interpretive gaps that prevent direct extrapolation of rodent findings to human hepatic neurobiology. Finally, we propose a translational roadmap toward a standardized human hepatic neural atlas that integrates 3D structural mapping with molecular identity and functional validation. This synthesis argues that understanding the liver as a spatially organized neural organ is essential for the rational design of neuromodulatory therapies targeting metabolic, inflammatory, and fibrotic liver disease, and it outlines how this framework could inform neural biomarkers, disease classification, and sex-aware precision medicine.