️ Episode 176: FAHD1 and the Pyruvate-Driven Evolution of Hepatocellular Carcinoma

In this episode of PaperCast Base by Base, we explore how multi-omics integration—spanning single-cell transcriptomics, spatial mapping, and causal genetic inference—uncovers a pyruvate-hyperactive epithelial subpopulation in hepatocellular carcinoma and identifies FAHD1 as a central regulator linked to poor prognosis and immune evasion.

Study Highlights:
The authors harmonized six single-cell metabolic scoring methods across tens of thousands of tumor microenvironment cells and uncovered PyHighEpi cells with elevated pyruvate metabolism, stemness, and proliferation that concentrate in tumor cores. Spatial transcriptomics traced evolutionary trajectories from stromal transition zones into malignant foci and showed that pyruvate activity scales with spatial progression. Summary data-based Mendelian randomization pinpointed FAHD1 as a causal driver of HCC susceptibility, and FAHD1+ epithelial cells engaged cancer‑associated fibroblasts via ITGB2 to sculpt a TGF‑β/VEGF‑enriched niche consistent with immune escape. Functional knockdown experiments reduced proliferation, migration, and invasion, while an eight‑gene FAHD1‑derived risk score stratified survival and predicted responsiveness to PD‑1 blockade; in silico docking also suggested tivozanib as a potential FAHD1‑targeting compound.

Conclusion:
By linking mitochondrial pyruvate control to stromal crosstalk and immune suppression, the study positions FAHD1 as a therapeutic entry point and proposes risk-guided, metabolism‑plus‑immunity strategies for difficult‑to‑treat HCC.

Reference:
Huang, J., Liang, S., Sun, J., & Chen, H. (2025). FAHD1‑mediated pyruvate metabolism in hepatocellular carcinoma: Multi‑omics and causal genetic evidence. *Human Genetics and Genomics Advances*, 6, 100494. https://doi.org/10.1016/j.xhgg.2025.100494

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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