Integrative multi-omics analysis links FADS3 to HCC risk, tumor–stromal crosstalk, and prognosis

Hepatocellular carcinoma (HCC) accounts for the majority of liver cancers. Similar to other malignancies, HCC cells undergo profound metabolic reprogramming. Beyond the well-known Warburg effect, increasing attention has been directed toward abnormal alterations in fatty acid metabolism. Nonetheless, the impact of fatty acid metabolism in HCC remains incompletely understood. We used summary-data-based Mendelian randomization (SMR) to identify fatty acid metabolic process (FAMP)-related candidate genes associated with HCC risk. Single-cell RNA sequencing and spatial transcriptomic analyses were subsequently performed to characterize FADS3 expression, predicted cell–cell communication, and spatial relationships. Survival modeling and immune microenvironment analyses were performed to assess the prognostic relevance of FADS3-related features. SMR suggested a genetically supported association between higher FADS3 expression and increased HCC risk. ScRNA-seq and spatial transcriptomic analyses indicated prominent predicted communication and a local spatial association between FADS3-positive malignant cells and cancer-associated fibroblasts (CAFs). Survival modeling and immune-related analyses indicated that FADS3-related features were associated with adverse prognosis. Our integrative analyses identify FADS3 as a candidate gene associated with HCC risk and suggest that FADS3-positive malignant cells may participate in CAF-related tumor–stromal crosstalk. FADS3-related molecular features were also associated with adverse prognosis. These findings provide a basis for further experimental investigation of FADS3 in HCC.