Toward AI Virtual Cells for Hepatology: Representation, Generation, Dynamics, and Intervention in Single-Cell Models

Abstract

``Single-cell and spatial atlases describe the healthy and diseased liver at high resolution, including lobular hepatocyte zonation, fibrotic macrophage-stellate niches, cholangiocyte reactions, immune remodeling, and hepatocellular carcinoma ecosystems. These maps show where cell states occur but do not, by themselves, predict whether liver injury will progress or how the liver will respond to an untested drug, toxicant, or genetic perturbation. In this review, we organize current approaches toward an AI Virtual Cell (AIVC) for the liver into three complementary modeling routes. Generative models represent cell states, dynamics and transport models infer state transitions, and pretrained or foundation models test whether learned representations transfer across donors, etiologies, disease stages, and platforms. Perturbation-response prediction serves as a cross-cutting assessment of whether these layers can predict responses to untested genetic, chemical, inflammatory, or metabolic interventions. Available evidence can be categorized as direct liver validation, liver-included benchmarks, general single-cell evidence, and conceptual applications. Published models demonstrate individual components, including atlas integration, inferred trajectories, transferable representations, and retrospective response programs. However, these models do not constitute a prospectively validated liver simulator. At minimum, evaluation should include donor-, etiology-, stage-, platform-, and perturbation-level hold-outs. Model performance should be reported using response direction, recovery of differentially expressed genes and rare states, and calibrated uncertainty. Claims about tissue- or function-level prediction additionally require independent spatial, histologic, metabolic, and functional readouts. Near-term use should prioritize experiment selection and hypothesis generation, whereas clinical decision support remains a longer-term objective.