FAHD1-mediated pyruvate metabolism in hepatocellular carcinoma: Multi-omics and causal genetic evidence.

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 ce

SUBMITTER: Huang J 

PROVIDER: S-EPMC12414894 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature