Abstract
Hepatocellular carcinoma (HCC) progression is driven by metabolic reprogramming in the tumor microenvironment (TME), yet the causal regulators of pyruvate metabolism and their spatial interplay remain elusive. Here, we integrate single-cell transcriptomics, spatial mapping, and genetic causal inference to identify a pyruvate-hyperactive epithelial subpopulation (PyHighEpi) in HCC, characterized by enhanced stemness, proliferation, and metastatic traits. Spatial analyses reveal metabolic zonation, with pyruvate activity concentrated in tumor cores and associated with aggressive clones. Summary data-based Mendelian randomization identifies fumarylacetoacetate hydrolase domain containing 1 (FAHD1) as a potential causal driver, with its expression associated with a poor prognosis. FAHD1+epi cells interact with cancer-associated fibroblasts through ITGB2-mediated interactions, facilitating the formation of a transforming growth factor-β/vascular endothelial growth factor-enriched niche that promotes immune evasion. Clinically, FAHD1 overexpression correlated with poor prognosis, validated through functional assays showing its knockdown suppressed proliferation, invasion, and migration in HCC models. An FAHD1-derived risk score robustly stratifies patient prognosis and predicts responsiveness to immunotherapy, while molecular docking highlighted tivozanib as a potential FAHD1-targeting agent.